Antiviral Compounds with a Heterotricycle Moiety

ABSTRACT

Disclosed are compounds of formula (I) for use as antiviral agents, particularly as anti-hepatitis virus C agents, wherein A, B, U, R 1 -R 7 , m, n, and q are as described herein. Also disclosed are pharmaceutical compositions and methods of treating or preventing viral infection in a host by the use of these compounds, either alone or in combination with other pharmaceutically active agents. Further disclosed are methods of preparing such compounds.

FIELD OF THE INVENTION

The present invention relates to antiviral compounds, their tautomericforms, their stereoisomers, and their pharmaceutically acceptable salts,pharmaceutical compositions comprising one or more such compounds, andmethods of treating viral infection.

CROSS-REFERENCE TO A RELATED APPLICATION

The present application claims the benefit of Indian Provisional PatentApplication Nos. 0147/KOL/2012 filed 10 Feb. 2012, and 1017/KOL/2012filed 4 Sep. 2012, the disclosure of which is incorporated herein byreference in its entirety.

BACKGROUND OF THE INVENTION

Persistent hepatitis C virus (HCV) infection is a major health problemglobally affecting ˜3% of the world population and is an importantcontributor to chronic liver disease culminating with liver cirrhosis,hepatocellular carcinoma and liver failure [Szabo E, Lotz G, et al.,Pathol. Oncol. Res., 2003, 9, 215-221; Hoofnagle J H., Hepatology, 1997,26 15S-20]. An estimated 170 million chronic carriers worldwide are atrisk of developing liver disease. In the United States alone ˜3 millionare chronically infected with HCV and the number of HCV related deathsis increasing significantly over the years [Barnes E., WHO factsheet2010. Available at:http://www.who.int/vaccine_research/diseases/viral_cancers/en/index2.html].Clinically, chronic infection is often asymptomatic with latent periodslasting for decades before manifestation by which time extensive liverdamage has occurred. HCV is spread primarily by unscreened bloodtransfusions and use of contaminated needles and syringes; the highestrisk groups are intravenous drug users and people who received bloodtransfusions (mainly haemophiliacs) before 1990 when screening for HCVwas introduced. Factors that have been reported to influence the rate ofHCV disease progression include age (increasing age is associated withmore rapid progression), gender (males have more rapid diseaseprogression than females), alcohol consumption (associated with anincreased rate of disease progression), HIV co-infection (associatedwith a markedly increased rate of disease progression), and fatty liver.

The standard therapy for HCV was a combination of pegylated interferon(PEG-IFN) α and weight based ribavarin (RBV), which was inadequate formajority of the patients and therapy associated side effects such aspancytopenia, flu-like symptoms or depression were commonly observedleading to early treatment discontinuation [Fried M W, et al., N. Engl.J. Med., 2002, 347, 975-982]. The approval of two direct acting agents(DAA), i.e., 1^(st) generation protease inhibitors, Incivek andVictrelis in May 2011 ushered in the era of specifically targeted HCVtherapy [Jesudian A B, Gambarin-Gelwan M and Jacobson I M.,Gastroenterology Hepatol. 2012, 8, 91-101].

The combination of above mentioned DAAs, PEG-IFN and RBV (tripletherapy) substantially increased the rate of sustained virologicresponse in the treatment nave and experienced patients. However, anumber of issues restrict the usage of these drugs—i) complex treatmentalgorithms issued by the regulatory bodies; ii) they are restricted togenotype 1; iii) low barrier to resistance mutations and/or iv)increased cost of therapy leading to only limited access to care. Hence,there exists a need for alternative therapeutic strategies that providea broader genotype coverage, better efficacy, better tolerance and/orlimited selection of resistant HCV variants.

The sequence diversity of HCV is complex with the virus organized into 6distinct genotypes and over 100 subtypes. Additionally, HCV exists asmany closely related viral sequences, termed as quasi-species, in theinfected individual, making specific pharmaceutical targeting of HCVproteins challenging due to the rapid evolution of escape mutants. It isincreasingly evident that a broad collection of specific, pan genotypicanti-viral drugs targeting multiple essential viral functions, inaddition to the current viral therapies, will be required for effectiveglobal control of HCV.

Disclosures describing HCV inhibitors include US 2009/0202478, US2009/0202483, WO 2009/020828, WO 2009/020825, WO 2009/102318, WO2009/102325, WO 2009/102694, WO 2008/144380, WO 2008/021927, WO2008/021928, WO 2008/021936, WO 2006/133326, WO 2004/014852, WO2008/070447, WO 2009/034390, WO 2006/079833, WO 2007/031791, WO2007/070556, WO 2007/070600, WO 2008/064218, WO 2008/154601, WO2007/082554, WO 2008/048589, EP 2121697, U.S. Pat. No. 8,008,264, U.S.Pat. No. 8,008,263, US 2011/0217265, US 2011/0217261, U.S. Pat. No.8,012,982, U.S. Pat. No. 8,012,942, U.S. Pat. No. 8,012,941, US2011/0223134, WO 2011/106992, WO 2011/106929, US 2011/0237636, US2011/0237579, US 2011/0236348, US 2011/0250176, US 2011/0250172, US2011/269956, US 2011/274648, EP 2385048, US 2011/0281910, US2011/0286961, US 2011/0294819, US 2011/0293563, US 2011/300104, WO2011/156543, WO 2011/153396, WO 2011/151652, WO 2011/151651, US2012/004196, U.S. Pat. No. 8,093,243, U.S. Pat. No. 8,101,643, US2012/0028978, WO 2012/018534, WO 2012/018325, WO 2012/021704, WO2012/021591, US 2012/004/0977, US 2012/004/0962, WO 2012/024363, EP2086995, EP 2049116, U.S. Pat. No. 8,133,884, US 2012/0076755, EP2250163, U.S. Pat. No. 8,143,414, U.S. Pat. No. 8,143,301, U.S. Pat. No.8,143,288, US 2012/0083483, U.S. Pat. No. 8,147,818, WO 2012/039717, WO2012/041227, WO 2012/041014, EP 2146984, U.S. Pat. No. 8,188,132, andU.S. Pat. No. 8,198,449, the disclosures of which are incorporated byreference.

BRIEF SUMMARY OF THE INVENTION

The present invention provides antiviral compounds of the generalformula (I):

their tautomeric forms, their isomers, their pharmaceutically acceptablesalts, pharmaceutical composition containing them, methods of making theabove compounds, and their use as antiviral compounds; wherein A, B, U,and R¹-R⁷, m, n, and q are described in detail below.

According to one aspect of the present invention there is providedcompounds represented by the general formula I, its tautomeric forms,its stereoisomers, its pharmaceutically acceptable salts, theircombinations with suitable medicament and pharmaceutical compositionscontaining them having a broader spectrum of activity as they showinhibitory actions against multiple genotypes of HCV with high potency.

The present invention also provide compounds represented by the generalformula I, its tautomeric forms, its stereoisomers, its pharmaceuticallyacceptable salts, their combinations with suitable medicament andpharmaceutical compositions containing them having good stability inhuman liver microsomes and promising oral bioavailability with enhancedliver concentrations and high liver to plasma ratio.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides compounds of the general formula (I):

their tautomeric forms, their isomers, their pharmaceutically acceptablesalts, pharmaceutical composition containing them, methods of making ofthe above compounds, and their use as antiviral compounds;wherein,A is selected from —CR⁷═, —C(H)(R⁷)— and —O—;B is selected from —C(R⁷)═ and —S—;U is selected from —N═ and —S—;with a proviso that B and U both cannot be S at the time;“

” represents a single or double bond;R¹ and R⁴ are divalent groups, each of which along with the respectivecarbon atoms to which they are attached form a 3 to 7 memberedcarbocyclic ring or a 5 to 7 membered heterocyclic ring containingnitrogen, and optionally oxygen;R² and R³ are each independently selected from hydrogen, substituted- orunsubstituted-alkyl, substituted- or unsubstituted-cycloalkyl,substituted- or unsubstituted-aryl, substituted- orunsubstituted-heteroaryl, substituted- or unsubstituted-heterocyclyl,R^(8a)C(═O)—, R^(8a)S(═O)₂—, R^(8a)OC(═O)—, (R⁹)R⁸NC(═O)—,R^(8a)OC(═O)N(R⁹)CR^(b)(R^(a))C(═O)—,R^(8a)OC(═O)N(R⁹)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—,R^(8a)C(═O)N(R⁹)C(R^(b))(R^(a))C(═O)—,R^(8a)C(═O)N(R⁹)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—, (R⁹)R⁸NC)(═O)N(R¹⁰)C(R^(b))(R^(a))C(═O)—, andR⁹(R⁸)NC(═O)N(R¹⁰)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—;R⁵ and R⁶ are each independently selected from hydrogen, halogen,substituted- or unsubstituted-alkyl, and substituted- orunsubstituted-cycloalkyl;R⁷ is selected from hydrogen, halogen, and substituted- or unsubstitutedC₁₋₃ alkyl;R⁸ is selected from hydrogen, substituted- or unsubstituted-alkyl,substituted- or unsubstituted-cycloalkyl, substituted- orunsubstituted-aryl, substituted- or unsubstituted-heteroaryl, andsubstituted- or unsubstituted-heterocyclyl;R⁹ and R¹⁰ are each independently selected from hydrogen, substituted-or unsubstituted-alkyl;R^(8a) is independently selected from the group consisting ofsubstituted- or unsubstituted-alkyl, substituted- orunsubstituted-cycloalkyl, substituted- or unsubstituted-aryl,substituted- or unsubstituted-heteroaryl, and substituted- orunsubstituted-heterocyclyl;R^(a), R^(b), R^(c) and R^(d), are independently selected from hydrogen,substituted- or unsubstituted-C₁₋₆ alkyl, substituted- orunsubstituted-aryl, substituted- or unsubstituted-heteroaryl,substituted- or unsubstituted-cycloalkyl, and substituted- orunsubstituted-heterocyclyl, or R^(a), R^(b), R^(c) and R^(d) togetherwith the carbon atom(s) to which they are attached forming substituted-or unsubstituted-carbocycle, or substituted- orunsubstituted-heterocycle;m and n are integers independently selected from 0 and 1;q is an integer selected from 1, 2, and 3;when the alkyl group is a substituted alkyl group, the alkyl group issubstituted with 1 to 4 substituents selected independently from oxo,halogen, cyano, perhaloalkyl, cycloalkyl, aryl, heteroaryl,heterocyclyl, R^(11a)O—, (alkyl)S(═O)₂—, (alkyl)C(═O)—, (alkyl)OC(═O)—,(alkyl)C(═O)O—, R¹¹N(H)C(═O)—, R¹¹(alkyl)NC(═O)—, (alkyl)C(═O)N(H)—,R¹¹N(H)—, R¹¹(alkyl)N—, R¹¹(H)NC(═O)N(H)—, and R¹¹(alkyl) NC(═O)N(H)—;when the ‘cycloalkyl’ and the carbocyclic groups are substituted, eachof them is substituted with 1 to 3 substituents selected independentlyfrom oxo, halogen, cyano, C₁₋₆ alkyl, perhaloalkyl, R^(11a)O—,(alkyl)S(═O)₂—, (alkyl)C(═O)—, (alkyl)OC(═O)—, (alkyl)C(═O)O—,R¹¹(H)NC(═O)—, R¹¹(alkyl)NC(═O)—, (alkyl)C(═O)N(H)—, R¹¹(H)N—,R¹¹(alkyl)N—, R¹¹(H)NC(═O)N(H)—, and R¹¹(alkyl)NC(═O)N(H)—;when the aryl group is substituted, it is substituted with 1 to 3substituents selected independently from halogen, cyano, hydroxy, C₁₋₆alkyl, perhaloalkyl, alkyl-O—, perhaloalkyl-O—, alkyl(alkyl)N—,alkyl(H)N—, H₂N—, alkyl-S(═O)₂—, alkyl-C(═O)(alkyl)N—, alkyl-C(═O)N(H)—,alkyl(alkyl)NC(═O)—, alkyl(H)NC(═O)—, H₂NC(═O)—, alkyl(alkyl)NS(═O)₂—,alkyl(H)NS(═O)₂—, and H₂NS(═O)₂—;when the heteroaryl group is substituted, it is substituted with 1 to 3substituents selected independently from halogen, cyano, hydroxy, C₁₋₆alkyl, perhaloalkyl, alkyl-O—, perhaloalkyl-O—, alkyl(alkyl)N—,alkyl(H)N—, H₂N—, alkyl-S(═O)₂—, alkyl-C(═O)(alkyl)N—, alkyl-C(═O)N(H)—,alkyl(alkyl)NC(═O)—, alkyl(H)NC(═O)—, H₂NC(═O)—, alkyl(alkyl)NS(═O)₂—,alkyl(H)NS(═O)₂—, and H₂NS(═O)₂—;when the heterocyclic group is substituted, it can be substituted eitheron a ring carbon atom or on a ring hetero atom, when it substituted on aring carbon atom, it is substituted with 1-3 substituents selectedindependently from halogen, cyano, oxo, C₁₋₆ alkyl, perhaloalkyl,R^(11a)O—, (alkyl)OC(═O)—, (alkyl)C(═O)O—, R¹¹(H)NC(═O)—,R¹¹(alkyl)NC(═O)—, (alkyl)C(═O)N(H)—, R¹¹(H)N—, R¹¹(alkyl)N—,R¹¹(H)NC(═O)N(H)—, and R¹¹(alkyl)NC(═O)N(H)—; andwhen the ‘heterocyclic’ group is substituted on a ring nitrogen, it issubstituted with a substituent selected from —C₁₋₆ alkyl, (alkyl)SO₂—,(alkyl)C(═O)—, (alkyl)OC(═O)—, R¹¹(H)NC(═O)—, and R¹¹(alkyl)NC(═O)—;R¹¹ is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl;R^(11a) is selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl,aryl, heteroaryl, and heterocyclyl.

R¹ and R⁴ can be any suitable divalent groups, for example, C₁₋₄alkylenyl groups, particularly, —CH₂— or —CH₂CH₂—.

R² and R³ are each independently selected from R^(8a)C(═O)—,R^(8a)S(═O)₂—, R^(8a)OC(═O)—, (R⁹)R⁸NC(═O)—,R^(8a)OC(═O)N(R⁹)CR^(b)(R^(a))C(═O)—,R^(8a)OC(═O)N(R⁹)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—,R^(8a)C(═O)N(R⁹)C(R^(b))(R^(a))C(═O)—,R^(8a)C(═O)N(R⁹)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—,(R⁹)R⁸NC(═O)N(R¹⁰)C(R^(b))(R^(a))C(═O)—, andR⁹(R⁸)NC(═O)N(R¹⁰)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—.

R² and R³ are each independently selected fromR^(8a)OC(═O)N(R⁹)CR^(b)(R^(a))C(═O)—,R^(8a)OC(═O)N(R⁹)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—,R^(8a)C(═O)N(R⁹)C(R^(b)) (R^(a))C(═O)—,R^(8a)C(═O)N(R⁹)CR^(b)(R^(a))C(R^(d)) (R^(c))C(═O)—,(R⁹)R⁸NC(═O)N(R¹⁰)C(R^(b))(R^(a))C(═O)—, andR⁹(R⁸)NC(═O)N(R¹⁰)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—.

R² and R³ both are particularly selected asR^(8a)OC(═O)N(R⁹)CR^(b)(R^(a))C(═O)—.

R⁵ and R⁶ are each particularly selected from hydrogen and halogen;

Whenever a range of the number of atoms in a structure is indicated(e.g., a C₁₋₁₂, C₁₋₈, C₁₋₆, or C₁₋₄ alkyl, alkylamino, etc.), it isspecifically contemplated that any sub-range or individual number ofcarbon atoms falling within the indicated range also can be used. Thus,for instance, the recitation of a range of 1-8 carbon atoms (e.g.,C₁-C₈), 1-6 carbon atoms (e.g., C₁-C₆), 1-4 carbon atoms (e.g., C₁-C₄),1-3 carbon atoms (e.g., C₁-C₃), or 2-8 carbon atoms (e.g., C₂-C₈) asused with respect to any chemical group (e.g., alkyl, alkylamino, etc.)referenced herein encompasses and specifically describes 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, and/or 12 carbon atoms, as appropriate, as well asany sub-range thereof (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8carbon atoms, 1-9 carbon atoms, 1-10 carbon atoms, 1-11 carbon atoms,1-12 carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms,2-6 carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 2-9 carbon atoms,2-10 carbon atoms, 2-11 carbon atoms, 2-12 carbon atoms, 3-4 carbonatoms, 3-5 carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbonatoms, 3-9 carbon atoms, 3-10 carbon atoms, 3-11 carbon atoms, 3-12carbon atoms, 4-5 carbon atoms, 4-6 carbon atoms, 4-7 carbon atoms, 4-8carbon atoms, 4-9 carbon atoms, 4-10 carbon atoms, 4-11 carbon atoms,and/or 4-12 carbon atoms, etc., as appropriate).

One of the embodiments of the present invention is a compound of formula(Ia):

Another embodiment of the present invention is a compound of formula(Ib):

A further embodiment of the present invention is a compound of formula(Ic):

Yet another embodiment of the present invention is compound of formula(Id):

In any of the embodiments described above, R² and R³ both areparticularly selected as R^(8a)OC(═O)R⁹N(R^(b))R^(a)CC(═O)—.

In any of the embodiments described above, R⁵ and R⁶ are particularlyselected independently from hydrogen and halogen.

General terms used in the description of the formula above can bedefined as follows; however, the meaning stated should not beinterpreted as limiting the scope of the term per se.

The term “alkyl”, as used herein, means a straight or branchedhydrocarbyl chain containing from 1 to 20 carbon atoms. Preferably, thealkyl group contains 1 to 10 carbon atoms. More preferably, alkyl groupcontains up to 6 carbon atoms. Examples of alkyl groups include, but arenot limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n-hexyl.

In a substituted alkyl group, the alkyl group is substituted with 1 to 4substituents selected independently from oxo, halogen, cyano,perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, R^(11a)O—,(alkyl)S(═O)₂—, (alkyl)C(═O)—, (alkyl)OC(═O)—, (alkyl)C(═O)O—,R¹¹N(H)C(═O)—, R¹¹(alkyl)NC(═O)—, (alkyl)C(═O)N(H)—, R¹¹N(H)—,R¹¹(alkyl)N—, R¹¹(H)NC(═O)N(H)—, and R¹¹(alkyl)NC(═O)N(H)—; wherein, R¹¹is selected from hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl; and R^(11a) is selected from hydrogen, alkyl,perhaloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

The term “cycloalkyl” as used herein, means a monocyclic, bicyclic, ortricyclic non-aromatic ring system containing from 3 to 14 carbon atoms,preferably monocyclic cycloalkyl ring containing 3 to 6 carbon atoms.Examples of monocyclic ring systems include cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Bicyclic ringsystems include monocyclic ring system fused across a bond with anothercyclic system which may be an alicyclic ring or an aromatic ringBicyclic rings also include spirocyclic systems wherein the second ringgets annulated on a single carbon atom. Bicyclic ring systems are alsoexemplified by a bridged monocyclic ring system in which twonon-adjacent carbon atoms of the monocyclic ring are linked by analkylene bridge. Examples of bicyclic ring systems include, but are notlimited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, andbicyclo[4.2.1]nonane, bicyclo[3.3.2]decane, bicyclo[3.1.0]hexane,bicyclo[410]heptane, bicyclo[3.2.0]heptanes, octahydro-1H-indene,spiro[2.5]octane, spiro[4.5]decane,spiro[bicyclo[4.1.0]heptane-2,1′-cyclopentane],hexahydro-2′H-spiro[cyclopropane-1,1′-pentalene]. Tricyclic ring systemsare the systems wherein the bicyclic systems as described about arefurther annulated with third ring, which may be alicyclic ring oraromatic ring. Tricyclic ring systems are also exemplified by a bicyclicring system in which two non-adjacent carbon atoms of the bicyclic ringare linked by a bond or an alkylene bridge. Examples of tricyclic-ringsystems include, but are not limited to, tricyclo[3.3.1.0^(3.7)]nonaneand tricyclo[3.3.1.1^(3.7)]decane (adamantane).

The term “carbocycle” as used herein, means a cyclic system made up ofcarbon atoms, which includes cycloalkyl, cycloalkenyl and aryl.

When the cycloalkyl or the carbocyclic groups' are substituted, they aresubstituted with 1 to 3 substituents selected independently from oxo,halogen, cyano, C₁₋₆ alkyl, perhaloalkyl, R^(11a)O—, (alkyl)S(═O)₂—,(alkyl)C(═O)—, (alkyl)OC(═O)—, (alkyl)C(═O)O—, R¹¹(H)NC(═O)—,R¹¹(alkyl)NC(═O)—, (alkyl)C(═O)N(H)—, R¹¹(H)N—, R¹¹(alkyl)N—,R¹¹(H)NC(═O)N(H)—, and R¹¹(alkyl)NC(═O)N(H)—; wherein, R¹¹ is selectedfrom hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl;and R¹¹ is selected from hydrogen, alkyl, perhaloalkyl, cycloalkyl,aryl, heteroaryl, and heterocyclyl.

The term “aryl” refers to a monocyclic, bicyclic or tricyclic aromatichydrocarbon ring system. Examples of aryl groups include phenyl,naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like. Arylgroup also includes partially saturated bicyclic and tricyclic aromatichydrocarbons such as tetrahydro-naphthalene.

When the aryl group is substituted, it is substituted with 1 to 3substituents selected independently from halogen, nitro, cyano, hydroxy,C₁₋₆ alkyl, perhaloalkyl, alkyl-O—, perhaloalkyl-O—, alkyl(alkyl)N—,alkyl(H)N—, H₂N—, alkyl-S(═O)₂—, alkyl-C(═O)(alkyl)N—, alkyl-C(═O)N(H)—,alkyl(alkyl)NC(═O)—, alkyl(H)NC(═O)—, H₂NC(═O)—, alkyl(alkyl)NS(═O)₂—,alkyl(H)NS(═O)₂—, and H₂NS(═O)₂—.

The term “heteroaryl” refers to a 5-14 membered monocyclic, bicyclic, ortricyclic ring system having 1-4 ring heteroatoms selected from O, N, orS, and the remainder ring atoms being carbon with appropriate hydrogenatoms unless otherwise indicated), wherein at least one ring in the ringsystem is aromatic. Heteroaryl groups may be optionally substituted withone or more substituents. In one embodiment, 0, 1, 2, 3, or 4 atoms ofeach ring of a heteroaryl group may be substituted by a substituent.Examples of heteroaryl groups include, but not limited to pyridyl,1-oxo-pyrinyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl,imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl,pyridazinyl, pyrimidinyl, pyraAnyl, triazinyl, triazolyl, thiadiazolyl,isoquinolinyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl,tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl,benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyl, quinazolinyl,purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, andbenzo(b)thienyl, 2,3-thiadiazolyl, 1H-pyrazolo[5,1-c]-1,2,4-triazolyl,pyrrolo[3,4-d]-1,2,3-triazolyl, cyclopentatriazolyl,3H-pyrrolo[3,4-c]isoxazolyl, 2,3-dihydro-benzo[1,4]dioxin-6-yl,2,3-dihydro-benzo[1,4]dioxin-5-yl, 2,3-dihydro-benzofuran-5-yl,2,3-dihydro-benzofuran-4-yl, 2,3-dihydro-benzofuran-6-yl,2,3-dihydro-benzofuran-6-yl, 2,3-dihydro-1H-indol-5-yl,2,3-dihydro-1H-indol-4-yl, 2,3-dihydro-1H-indol-6-yl,2,3-dihydro-1H-indol-7-yl, benzo[1,3]dioxol-4-yl, benzo[1,3]dioxol-5-yl,1,2,3,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,2,3-dihydrobenzothien-4-yl, 2-oxoindolin-5-yl and the like.

When the heteroaryl group is substituted, it is substituted with 1 to 3substituents selected independently from halogen, nitro, cyano, hydroxy,C₁₋₆ alkyl, perhaloalkyl, alkyl-O—, perhaloalkyl-O—, alkyl(alkyl)N—,alkyl(H)N—, H₂N—, alkyl-S(═O)₂—, alkyl-C(═O)(alkyl)N—, alkyl-C(═O)N(H)—,alkyl(alkyl)NC(═O)—, alkyl(H)NC(═O)—, H₂NC(═O)—, alkyl(alkyl)NS(═O)₂—,alkyl(H)NS(═O)₂— and H₂NS(═O)₂—.

The term “heterocycle” or “heterocyclic” as used herein, means a‘cycloalkyl’ group wherein one or more of the carbon atoms replaced by—O—, —S—, —S(O₂)—, —S(O)—, —Si(R^(m))R^(n)—, wherein, R^(m) and R^(n)are independently selected from hydrogen, alkyl, aryl, heteroaryl,cycloalkyl, and heterocyclyl. The heterocycle may be connected to theparent molecular moiety through any carbon atom or any nitrogen atomcontained within the heterocycle. Examples of monocyclic heterocycleinclude, but are not limited to, azetidinyl, azepanyl, aziridinyl,diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl,thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl,1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, andtrithianyl. Examples of bicyclic heterocycle include, but are notlimited to 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl,2,3-dihydro-1H-indolyl and 1,2,3,4-tetrahydroquinolinyl. The termheterocycle also include bridged heterocyclic systems such asazabicyclo[3.2.1]octane, azabicyclo[3.3.1]nonane and the like.

The heterocyclic group, when it is substituted, it may be substituted ona ring carbon atom or a ring hetero atom. For example, it is substitutedon a ring carbon with 1-3 substituents selected independently fromhalogen, nitro, cyano, oxo, C₁₋₆ alkyl, perhaloalkyl, R^(11a)O—,(alkyl)OC(═O)—, (alkyl)C(═O)O—, R¹¹(H)NC(═O)—, R¹¹(alkyl)NC(═O)—,(alkyl)C(═O)N(H)—, R¹¹(H)N—, R¹¹(alkyl)N—, R¹¹(H)NC(═O)N(H)—, andR¹¹(alkyl)NC(═O)N(H)—; wherein, R¹¹ is selected from hydrogen, alkyl,cycloalkyl, aryl, heteroaryl, and heterocyclyl; and R^(11a) is selectedfrom hydrogen, alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, andheterocyclyl.

When the heterocyclic group is substituted on ring nitrogen, it issubstituted with a substituent selected from —C₁₋₆ alkyl, (alkyl)SO₂—,(alkyl)C(═O)—, (alkyl) OC(═O)—, R¹¹(H)NC(═O)—, and R¹¹(alkyl)NC(═O)—;wherein, R^(11a) is selected from hydrogen, alkyl, cycloalkyl, aryl,heteroaryl, and heterocyclyl; and R^(11a) is selected from hydrogen,alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl.

When a parent group is substituted with an “oxo” group, it means adivalent oxygen (═O) becomes attached to a carbon atom of the parentgroup. For example, when a CH₂ group is substituted with an oxosubstituent, the parent CH₂ group becomes a carbonyl (C═O) group; thus,oxo substituted on cyclohexane forms a cyclohexanone, for example.

The term “annulated” means the ring system under consideration is eitherannulated with another ring at a carbon atom of the cyclic system oracross a bond of the cyclic system as in the case of spiro or fused ringsystems.

The term “bridged” means the ring system under consideration contain analkylene bridge having 1 to 4 methylene units joining two non-adjacentring atoms.

In a specific embodiment, the invention provides a compound, itsstereoisomers, racemates, pharmaceutically acceptable salts thereof asdescribed hereinabove wherein the compound of general formula I isselected from:

-   1.    dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,9b-dihydro-3aH-thieno[3,2-c]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate    (Compound 1);-   2.    dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate    (Compound 2);-   3.    dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(4-chloro-1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate    (Compound 3);-   4.    dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(naphtho[1,2-d]thiazole-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate    (Compound 4);-   5.    dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate    (Compound 5);-   6.    dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(3-chloro-4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(4-chloro-1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate    (Compound 6);-   7.    dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate    (Compound 7);-   8.    dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate    (Compound 8);-   9.    dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)bis(4-chloro-1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate    (Compound 9);-   10.    dimethyl((2S,2′S)-((1R,1′R,3S,3'S,4S,4′S)-3,3′-(5,5′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-azabicyclo[2.2.1]heptane-3,2-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate    (Compound 10); and-   11. methyl((S)-1-((S)-2-(5-(2-(2-((1R,3    S,4S)-2-((S)-2-(methoxycarbonyl)amino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphtho[1,2-b]thiophen-7-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate    (Compound 11).

According to an embodiment of the present invention, the compounds ofgeneral formula (I) where all the symbols are as defined earlier can beprepared by methods illustrated in the schemes below and in theexamples. Representative procedures are shown below, however; thedisclosure should not be construed to limit the scope of the inventionarriving at compound of formula (I) as disclosed hereinabove.

Halogenation of 1 (synthesized according to methods described in EP1650202) using a halogenating agent such as bromine lead to theformation of 2, which on Stille coupling gives rise to compound 3.Alternately, direct Friedel Crafts acylation of 1 leads to the formation3. Halogenation of 3 using halogenating agents like NBS, NCS, NIS,bromine and iodine leads to the synthesis of 4 (where X=halogen) whichundergoes O-alkylation using Boc-L-proline leading to the formation of 5as shown in Scheme 1. Cyclization of 5 using a reagent like ammoniumacetate in toluene, xylene, or 1,4-dioxane leads to the formation of 6.The intermediate 6 thus obtained is deprotected under acidic conditionsand the amine thus obtained is coupled with acid such as(S)-2-[(methoxycarbonyl)-amino]-3-methylbutanoic acid using methodsknown in the art to generate the compounds of formula (I).

An alternative way for the synthesis of compound of general formula (I)containing the thiophene tricycle is illustrated in Scheme 2 and isstarting from a benzo fused cyclic ketone such as 7 and then convertingit to chloro vinyl aldehyde 8 by the Vilsmeier-Haack reaction. Basemediated cyclisation of 8 with mercaptoacetone generates the tricyclesuch as 9, which on Friedel Crafts acylation provides the diacetyltricycle 10. Alpha halogenation of the acetyl group or hydroxylationfollowed by protection in one step provides the intermediate 11(where Zdepicts leaving groups such as Br, I, Cl, OTs, OMs), which is furtherconverted to the compound of general formula (I) by a sequence ofO-alkylation, cyclisation, aromatisation (in case of aromatic tricycle)and peptide coupling as shown in Scheme 1.

For incorporating an oxygen atom in the middle ring of the tricycle, thestarting compound is bromobenzo fused pyranone or oxepanone 12, which isconverted to the chloro vinyl aldehyde 13 by the Vilsmeier-Haackreaction. Base mediated cyclisation of 13 with mercaptoacetone providestricycles such as 14. A Stille reaction on this intermediate providesthe diacetyl tricycle 15. Alpha halogenation of the acetyl group orhydroxylation followed by protection in one step provides theintermediate 16 (where Z depicts leaving groups such as Br, I, Cl, OTs,OMs), which is then converted to the compound of general formula (I) bya sequence of O-alkylation, cyclisation, and peptide coupling as shownin Scheme 1.

The intermediates and the compounds of the present invention areobtained, e.g., in pure form, in a manner known per se, for example bydistilling off the solvent in vacuum and re-crystallizing the residueobtained from a suitable solvent, such as pentane, diethyl ether,isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone ortheir combinations or subjecting it to one of the purification methods,such as column chromatography (e.g., flash chromatography) on a suitablesupport material such as alumina or silica gel using eluent such asdichloromethane, ethyl acetate, hexane, methanol, acetone and theircombinations. Preparative HPLC method is also used for the purificationof molecules described herein.

Salts of the compounds of formula (I) are obtained by dissolving thecompound in a suitable solvent, for example, a chlorinated hydrocarbon,such as methylene chloride or chloroform or a low molecular weightaliphatic alcohol, for example, ethanol or isopropanol, which is thentreated with the desired acid or base, for example, as described inBerge S. M. et al., “Pharmaceutical Salts, a review article,” Journal ofPharmaceutical Sciences, volume 66, page 1-19 (1977)” and in theHandbook of Pharmaceutical Salts—Properties, Selection, and Use, by P.H. Einrich Stahland Camille G. wermuth, Wiley—VCH (2002). Lists ofsuitable salts can also be found in Remington's Pharmaceutical Sciences,18th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445, andJournal of Pharmaceutical Science, 66, 2-19 (1977). For example, theycan be a salt of an alkali metal (e.g., sodium or potassium), alkalineearth metal (e.g., calcium), or ammonium salt.

The compound of the invention or a composition thereof can potentiallybe administered as a pharmaceutically acceptable acid-addition, baseneutralized or addition salt, formed by reaction with inorganic acids,such as hydrochloric acid, hydrobromic acid, perchloric acid, nitricacid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organicacids such as formic acid, acetic acid, propionic acid, glycolic acid,lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid,maleic acid, and fumaric acid, or by reaction with an inorganic base,such as sodium hydroxide, potassium hydroxide. The conversion to a saltis accomplished by treatment of the base compound with at least astoichiometric amount of an appropriate acid. Typically, the free baseis dissolved in an inert organic solvent such as diethyl ether, ethylacetate, chloroform, ethanol, methanol, and the like, and the acid isadded in a similar solvent. The mixture is maintained at a suitabletemperature (e.g., between 0° C. and 50° C.). The resulting saltprecipitates spontaneously or can be brought out of solution with a lesspolar solvent.

The stereoisomers of the compounds of formula I of the present inventionmay be prepared by stereospecific synthesis or resolution of the racemiccompound using an optically active amine, acid or complex forming agent,and separating the diastereomeric salt/complex by fractionalcrystallization or by column chromatography.

The compounds of the invention, their tautomeric forms, theirstereoisomers, their pharmaceutically acceptable salts, theircombinations with suitable medicament and pharmaceutical compositionscontaining them exhibited a broader spectrum of activity as they showinhibitory actions against multiple genotypes of HCV with high potency.

The compounds of the invention, their tautomeric forms, theirstereoisomers, their pharmaceutically acceptable salts, theircombinations with suitable medicament and pharmaceutical compositionscontaining them, have demonstrated good stability in human livermicrosomes and exhibited promising oral bioavailability in preclinicalspecies with enhanced liver concentrations and high liver to plasmaratio.

Compounds of the present invention were prepared using synthetic schemesprovided below:

Compounds 1 to 3 were prepared by following the route illustrated inScheme I:

Compound 4 was prepared by following the route illustrated in Scheme II:

Compounds 5-9 were prepared by following the route illustrated in SchemeIII:

Compound 10 was prepared by following the route illustrated in SchemeIV:

Compound 11 was prepared by following the route illustrated in Scheme V:

A further embodiment of the present invention includes pharmaceuticalcompositions comprising any single compound, a tautomer, or isomerthereof, a combination of two or more compounds delineated herein,tautomers, or isomers thereof, or a pharmaceutically acceptable salt orsalts thereof, with a pharmaceutically acceptable carrier or excipient.

Yet a further embodiment of the present invention is a pharmaceuticalcomposition comprising any single compound, a tautomer, or isomerthereof, or a combination of two or more compounds delineated herein,tautomers, or isomers thereof, or a pharmaceutically acceptable salt orsalts thereof, in combination with one or more agents known in the art,with a pharmaceutically acceptable carrier or excipient.

The pharmaceutically acceptable carrier (or excipient) is preferably onethat is chemically inert to the compound of the invention and one thathas no detrimental side effects or toxicity under the conditions of use.Such pharmaceutically acceptable carriers preferably include saline(e.g., 0.9% saline), Cremophor EL (which is a derivative of castor oiland ethylene oxide available from Sigma Chemical Co., St. Louis, Mo.)(e.g., 5% Cremophor EL/5% ethanol/90% saline, 10% Cremophor EL/90%saline, or 50% Cremophor EL/50% ethanol), propylene glycol (e.g., 40%propylene glycol 10% ethanol/50% water), polyethylene glycol (e.g., 40%PEG 400/60% saline), and alcohol (e.g., 40% ethanol/60% water). Apreferred pharmaceutical carrier is polyethylene glycol, such as PEG400, and particularly a composition comprising 40% PEG 400 and 60% wateror saline. The choice of carrier will be determined in part by theparticular compound chosen, as well as by the particular method used toadminister the composition. Accordingly, there is a wide variety ofsuitable formulations of the pharmaceutical composition of the presentinvention.

The formulations for oral, aerosol, parenteral, subcutaneous,intravenous, intra-arterial, intramuscular, inter-peritoneal, rectal,and vaginal administration are merely exemplary and are in no waylimiting.

The pharmaceutical compositions can be administered parenterally, e.g.,intravenously, intra-arterially, subcutaneously, intra-dermally,intra-thecally, or intramuscularly. Thus, the invention providescompositions for parenteral administration that comprise a solution ofthe compound of the invention dissolved or suspended in an acceptablecarrier suitable for parenteral administration, including aqueous andnon-aqueous, isotonic sterile injection solutions.

Overall, the requirements for effective pharmaceutical carriers forparenteral compositions are well known to those of ordinary skill in theart. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company,Philadelphia, Pa., Banker and Chalmers, eds., pages 238-250 (1982), andASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630(1986). Such compositions include solutions containing anti-oxidants,buffers, bacteriostats, and solutes that render the formulation isotonicwith the blood of the intended recipient, and aqueous and non-aqueoussterile suspensions that can include suspending agents, solubilizers,thickening agents, stabilizers, and preservatives. The compound can beadministered in a physiologically acceptable diluent in a pharmaceuticalcarrier, such as a sterile liquid or mixture of liquids, includingwater, saline, aqueous dextrose and related sugar solutions, an alcohol,such as ethanol, isopropanol (for example in topical applications), orhexadecyl alcohol, glycols, such as propylene glycol or polyethyleneglycol, dimethylsulfoxide, glycerol ketals, such as2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, such aspoly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester orglyceride, or an acetylated fatty acid glyceride with or without theaddition of a pharmaceutically acceptable surfactant, such as a soap ora detergent, suspending agent, such as pectin, carbomers,methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agents and other pharmaceuticaladjuvants.

Oils useful in parenteral formulations include petroleum, animal,vegetable, and synthetic oils. Specific examples of oils useful in suchformulations include peanut, soybean, sesame, cottonseed, corn, olive,petrolatum, and mineral oil. Suitable fatty acids for use in parenteralformulations include oleic acid, stearic acid, and isostearic acid.Ethyl oleate and isopropyl myristate are examples of suitable fatty acidesters.

Suitable soaps for use in parenteral formulations include fatty alkalimetal, ammonium, and triethanolamine salts, and suitable detergentsinclude (a) cationic detergents such as, for example, dimethyl dialkylammonium halides, and alkyl pyridinium halides, (b) anionic detergentssuch as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin,ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionicdetergents such as, for example, fatty amine oxides, fatty acidalkanolamides, and polyoxyethylene polypropylene copolymers, (d)amphoteric detergents such as, for example, alkyl-β-aminopropionates,and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixturesthereof.

The parenteral formulations typically will contain from about 0.5% orless to about 25% or more by weight of a compound of the invention, atautomer, or isomer thereof, or salt thereof in solution. Preservativesand buffers can be used. In order to minimize or eliminate irritation atthe site of injection, such compositions can contain one or morenonionic surfactants having a hydrophile-lipophile balance (HLB) of fromabout 12 to about 17. The quantity of surfactant in such formulationswill typically range from about 5% to about 15% by weight. Suitablesurfactants include polyethylene sorbitan fatty acid esters, such assorbitan monooleate and the high molecular weight adducts of ethyleneoxide with a hydrophobic base, formed by the condensation of propyleneoxide with propylene glycol. The parenteral formulations can bepresented in unit-dose or multi-dose sealed containers, such as ampoulesand vials, and can be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid excipient, forexample, water, for injections, immediately prior to use. Extemporaneousinjection solutions and suspensions can be prepared from sterilepowders, granules, and tablets.

Formulations suitable for oral administration can consist of (a) liquidsolutions, such as an effective amount of a compound of the invention, atautomer, or isomer thereof, or salt thereof, dissolved in diluents,such as water, saline, or orange juice; (b) capsules, sachets, tablets,lozenges, and troches, each containing a pre-determined amount of thecompound of the invention, a tautomer, or isomer thereof, or saltthereof, as solids or granules; (c) powders; (d) suspensions in anappropriate liquid; and (e) suitable emulsions. Liquid formulations caninclude diluents, such as water and alcohols, for example, ethanol,benzyl alcohol, and the polyethylene alcohols, either with or withoutthe addition of a pharmaceutically acceptable surfactant, suspendingagent, or emulsifying agent. Capsule forms can be of the ordinary hard-or soft-shelled gelatine type containing, for example, surfactants,lubricants, and inert fillers, such as lactose, sucrose, calciumphosphate, and cornstarch. Tablet forms can include one or more oflactose, sucrose, mannitol, corn starch, potato starch, alginic acid,microcrystalline cellulose, acacia, gelatine, guar gum, colloidalsilicon dioxide, croscarmellose sodium, talc, magnesium stearate,calcium stearate, zinc stearate, stearic acid, and other excipients,colorants, diluents, buffering agents, disintegrating agents, moisteningagents, preservatives, flavoring agents, and pharmacologicallycompatible excipients. Lozenge forms can comprise the compoundingredient in a flavor, usually sucrose and acacia or tragacanth, aswell as pastilles comprising a compound of the invention in an inertbase, such as gelatine and glycerine, or sucrose and acacia, emulsions,gels, and the like containing, in addition to the compound of theinvention, such excipients as are known in the art.

A compound of the present invention, a tautomer, or isomer thereof, orsalt thereof, alone or in combination with other suitable components,can be made into aerosol formulations to be administered via inhalation.A compound of the invention, a tautomer, or isomer thereof, or saltthereof, is preferably supplied in finely divided form along with asurfactant and propellant. Typical percentages of the compounds of theinvention can be about 0.01% to about 20% by weight, preferably about 1%to about 10% by weight. The surfactant must, of course, be nontoxic, andpreferably soluble in the propellant. Representative of such surfactantsare the esters or partial esters of fatty acids containing from 6 to 22carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic,linoleic, linolenic, olesteric and oleic acids with an aliphaticpolyhydric alcohol or its cyclic anhydride. Mixed esters, such as mixedor natural glycerides can be employed. The surfactant can constitutefrom about 0.1% to about 20% by weight of the composition, preferablyfrom about 0.25% to about 5%. The balance of the composition isordinarily propellant. A carrier can also be included as desired, e.g.,lecithin, for intranasal delivery. These aerosol formulations can beplaced into acceptable pressurized propellants, such asdichlorodifluoromethane, propane, nitrogen, and the like. They also canbe formulated as pharmaceuticals for non-pressured preparations, such asin a nebulizer or an atomizer. Such spray formulations can be used tospray mucosa.

Additionally, the compound of the invention, a tautomer, or isomerthereof, or salt thereof, can be made into suppositories by mixing witha variety of bases, such as emulsifying bases or water-soluble bases.Formulations suitable for vaginal administration can be presented aspessaries, tampons, creams, gels, pastes, foams, or spray formulascontaining, in addition to the compound ingredient, such carriers as areknown in the art to be appropriate.

The concentration of the compound, a tautomer, or isomer thereof, orsalt thereof, in the pharmaceutical formulations can vary, e.g., fromless than about 1% to about 10%, to as much as 20% to 50% or more byweight, and can be selected primarily by fluid volumes, and viscosities,in accordance with the particular mode of administration selected.

For example, a typical pharmaceutical composition for intravenousinfusion could be made up to contain 250 ml of sterile Ringer'ssolution, and 100 mg of at least one compound, a tautomer, or isomerthereof, or salt thereof, of the invention. Actual methods for preparingparenterally administrable compounds of the invention will be known orapparent to those skilled in the art and are described in more detailin, for example, Remington's Pharmaceutical Science (17th ed., MackPublishing Company, Easton, Pa., 1985).

It will be appreciated by one of ordinary skill in the art that, inaddition to the afore-described pharmaceutical compositions, thecompound of the invention, a tautomer, or isomer thereof, or saltthereof, can be formulated as inclusion complexes, such as cyclodextrininclusion complexes, or liposomes. Liposomes can serve to target acompound of the invention to a particular tissue, such as lymphoidtissue or cancerous hepatic cells. Liposomes can also be used toincrease the half-life of a compound of the invention. Many methods areavailable for preparing liposomes, as described in, for example, Szokaet al., Ann. Rey. Biophys. Bioeng., 9, 467 (1980) and U.S. Pat. Nos.4,235,871, 4,501,728, 4,837,028, and 5,019,369.

The compounds of the invention, a tautomer, or isomer thereof, or saltthereof, can be administered in a dose sufficient to treat the disease,condition or disorder. Such doses are known in the art (see, forexample, the Physicians' Desk Reference (2004)). The compounds can beadministered using techniques such as those described in, for example,Wasserman et al., Cancer, 36, pp. 1258-1268 (1975) and Physicians' DeskReference, 58th ed., Thomson P D R (2004).

Suitable doses and dosage regimens can be determined by conventionalrange-finding techniques known to those of ordinary skill in the art.Generally, treatment is initiated with smaller dosages that are lessthan the optimum dose of the compound of the present invention.Thereafter, the dosage is increased by small increments until theoptimum effect under the circumstances is reached. The present methodcan involve the administration of about 0.1 ρg to about 50 mg of atleast one compound of the invention per kg body weight of theindividual. For a 70 kg patient, dosages of from about 10 ρg to about200 mg of the compound of the invention would be more commonly used,depending on a patient's physiological response.

By way of example and not intending to limit the invention, the dose ofthe pharmaceutically active agent(s) described herein for methods oftreating or preventing a disease or condition as described above can beabout 0.001 to about 1 mg/kg body weight of the subject per day, forexample, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5mg, 0.75 mg, or 1 mg/kg body weight per day. The dose of thepharmaceutically active agent(s) described herein for the describedmethods can be about 1 to about 1000 mg/kg body weight of the subjectbeing treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500mg, 750 mg, or 1000 mg/kg body weight per day.

In accordance with embodiments, the present invention provides methodsof treating, preventing, ameliorating, and/or inhibiting a hepatitis Cvirus infection comprising administering a compound of formula (I) or asalt thereof.

The compounds of the present invention are effective against the HCV 1band 2a genotypes. It should also be understood that the compounds of thepresent invention can inhibit multiple genotypes of the HCV. Hence, inaccordance with an embodiment of the invention, the compounds of thepresent invention are active against the 1a, 1b, 2a, 2b, 3a, 4a, and 5agenotypes of the HCV.

The terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well aswords stemming therefrom, as used herein, do not necessarily imply 100%or complete treatment, prevention, amelioration, or inhibition. Rather,there are varying degrees of treatment, prevention, amelioration, andinhibition of which one of ordinary skill in the art recognizes ashaving a potential benefit or therapeutic effect. In this respect, theinventive methods can provide any amount of any level of treatment,prevention, amelioration, or inhibition of the disorder in a mammal. Forexample, a disorder, including symptoms or conditions thereof, may bereduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,or 10%. Furthermore, the treatment, prevention, amelioration, orinhibition provided by the inventive method can include treatment,prevention, amelioration, or inhibition of one or more conditions orsymptoms of the disorder. Also, for purposes herein, “treatment,”“prevention,” “amelioration,” or “inhibition” can encompass delaying theonset of the disorder, or a symptom or condition thereof.

In accordance with the invention, the term subject includes an “animal”which in turn includes a mammal such as, without limitation, the orderRodentia, such as mice, and the order Lagomorpha, such as rabbits. It ispreferred that the mammals are from the order Carnivora, includingFelines (cats) and Canines (dogs). It is more preferred that the mammalsare from the order Artiodactyla, including Bovines (cows) and Swine(pigs) or of the order Perssodactyla, including Equines (horses). It ismost preferred that the mammals are of the order Primates, Ceboids, orSimoids (monkeys) or of the order Anthropoids (humans and apes). Anespecially preferred mammal is the human.

The term “viral infection” refers to the introduction of a virus intocells or tissues, e.g., hepatitis C virus (HCV). In general, theintroduction of a virus is also associated with replication. Viralinfection may be determined by measuring virus antibody titer in samplesof a biological fluid, such as blood, using, e.g., enzyme immunoassay.Other suitable diagnostic methods include molecular based techniques,such as RT-PCR, direct hybrid capture assay, nucleic acid sequence basedamplification, and the like. A virus may infect an organ, e.g., liver,and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease andhepatocellular carcinoma.

The term “immune modulator” refers to any substance meant to alter theworking of the humoral or cellular immune system of a subject. Suchimmune modulators include inhibitors of mast cell-mediated inflammation,interferons, interleukins, prostaglandins, steroids, cortico-steroids,colony-stimulating factors, chemotactic factors, etc.

It will be further appreciated that compounds of the present inventioncan be administered as the sole active pharmaceutical agent, or used incombination with one or more agents to treat or prevent hepatitis Cinfections or the symptoms associated with HCV infection. Other agentsto be administered in combination with a compound or combination ofcompounds of the present invention include therapies for diseases causedby HCV infection that suppresses HCV viral replication by direct orindirect mechanisms. These agents include, but not limited to, hostimmune modulators (for example, interferon-alpha, pegylatedinterferon-alpha, consensus interferon, interferon-beta,interferon-gamma, CpG oligonucleotides and the like); antiviralcompounds that inhibit host cellular functions such as inosinemonophosphate dehydrogenase (for example, ribavirin and the like);cytokines that modulate immune function (for example, interleukin 2,interleukin 6, and interleukin 12); a compound that enhances thedevelopment of type 1 helper T cell response; interfering RNA;anti-sense RNA; vaccines comprising HCV antigens or antigen adjuvantcombinations directed against the HCV; agents that interact with hostcellular components to block viral protein synthesis by inhibiting theinternal ribosome entry site (IRES) initiated translation step of HCVviral replication or to block viral particle maturation and release withagents targeted toward the viroporin family of membrane proteins suchas, for example, HCV P7 and the like; and any agent or combination ofagents that inhibit the replication of HCV by targeting other proteinsof the viral genome involved in the viral replication and/or interferewith the function of other viral targets, such as inhibitors of NS3NS4Aprotease, NS3 helicase, NS5B polymerase, NS4A protein and NS5A protein.

According to yet another embodiment, the pharmaceutical compositions ofthe present invention may further comprise inhibitor(s) of other targetsin the HCV life cycle, including, but not limited to, helicase,polymerase, metalloprotease, NS4A protein, NS5A protein, and internalribosome entry site (IRES).

Accordingly, one embodiment of the present invention is directed to amethod for treating or preventing an infection caused by anRNA-containing virus comprising co-administering to a patient in need ofsuch treatment one or more agents selected from the group consisting ofa host immune modulator and a second or more antiviral agents, or acombination thereof, with a therapeutically effective amount of acompound or combination of compounds of the present invention, or apharmaceutically acceptable salt thereof. Examples of the host immunemodulator are, but not limited to, interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamma, acytokine, a vaccine, and a vaccine comprising an antigen and anadjuvant, and said second antiviral agent inhibits replication of HCVeither by inhibiting host cellular functions associated with viralreplication or by targeting proteins of the viral genome.

A further embodiment of the present invention is directed to a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment anagent or combination of agents that treat or alleviate symptoms of HCVinfection including cirrhosis and inflammation of the liver, with atherapeutically effective amount of a compound or combination ofcompounds of the present invention, or a pharmaceutically acceptablesalt thereof. Yet another embodiment of the present invention provides amethod of treating or preventing infection caused by an RNA-containingvirus comprising co-administering to a patient in need of such treatmentone or more agents that treat patients for disease caused by hepatitis B(HBV) infection, with a therapeutically effective amount of a compoundor a combination of compounds of the present invention, or apharmaceutically acceptable salt thereof. An agent that treats patientsfor disease caused by hepatitis B (HBV) infection may be for example,but not limited thereto, L-deoxythymidine, adefovir, lamivudine ortenofovir, or any combination thereof.

A further embodiment of the present invention provides a method oftreating or preventing infection caused by an RNA-containing viruscomprising co-administering to a patient in need of such treatment oneor more agents that treat patients for disease caused by humanimmunodeficiency virus (HIV) infection, with a therapeutically effectiveamount of a compound or a combination of compounds of the presentinvention, or a pharmaceutically acceptable salt thereof. The agent thattreats patients for disease caused by human immunodeficiency virus (HIV)infection may include, but is not limited thereto, ritonavir, lopinavir,indinavir, nelfmavir, saquinavir, amprenavir, atazanavir, tipranavir,TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine,tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine,TMC-125, L-870812, S-1360, enfuvirtide (T-20) or T-1249, or anycombination thereof.

An example of the RNA-containing virus in any of the above embodimentsincludes, but not limited to, the hepatitis C virus (HCV).

It can occur that a patient may be co-infected with hepatitis C virusand one or more other viruses, including but not limited to humanimmunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis Bvirus (HBV). Thus also contemplated is a combination therapy to treatsuch co-infections by co-administering a compound according to thepresent invention with at least one of an HIV inhibitor, an HAVinhibitor and an HBV inhibitor.

In addition, the present invention provides the use of a compound or acombination of compounds of the invention, or a therapeuticallyacceptable salt thereof, and one or more agents selected from the groupconsisting of a host immune modulator and a second or more antiviralagents, or a combination thereof, to prepare a medicament for thetreatment of an infection caused by an RNA-containing virus in apatient, particularly hepatitis C virus. Examples of the host immunemodulators include, but are not limited to, interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamma, acytokine, a vaccine, and a vaccine comprising an antigen and anadjuvant, and said second antiviral agent inhibits replication of HCVeither by inhibiting host cellular functions associated with viralreplication or by targeting proteins of the viral genome.

When used in the above or other treatments, combination of compound orcompounds of the present invention, together with one or more agents asdefined herein above, can be employed in pure form or, where such formsexist, in pharmaceutically acceptable salt thereof. Alternatively, suchcombination of therapeutic agents can be administered as apharmaceutical composition containing a therapeutically effective amountof the compound or combination of compounds of interest, or theirpharmaceutically acceptable salt thereof, in combination with one ormore agents as defined hereinabove, and a pharmaceutically acceptablecarrier. Such pharmaceutical compositions can be used for inhibiting thereplication of an RNA-containing virus, particularly Hepatitis C virus(HCV), by contacting said virus with said pharmaceutical composition. Inaddition, such compositions are useful for the treatment or preventionof an infection caused by an RNA-containing virus, particularlyHepatitis C virus (HCV).

Hence, a still further embodiment of the invention is directed to amethod of treating or preventing infection caused by an RNA-containingvirus, particularly a hepatitis C virus (HCV), comprising administeringto a patient in need of such treatment a pharmaceutical compositioncomprising a compound or combination of compounds of the invention or apharmaceutically acceptable salt thereof, and one or more agents asdefined hereinabove, with a pharmaceutically acceptable carrier.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time orwithin a predetermined period of time, or the therapeutic agents can begiven as a single unit dosage form. The therapeutic agents can beadministered simultaneously, sequentially, or cyclically.

Antiviral agents contemplated for use in such combination therapyinclude agents (compounds or biologicals) that are effective to inhibitthe formation and/or replication of a virus in a mammal, including butnot limited to agents that interfere with either host or viralmechanisms necessary for the formation and/or replication of a virus ina mammal. Such agents can be selected from another anti-HCV agent; anHIV inhibitor; an HAV inhibitor; and an HBV inhibitor.

Other agents to be administered in combination with a compound of thepresent invention include a cytochrome P450 monooxygenase inhibitor,which is expected to inhibit metabolism of the compounds of theinvention. Therefore, the cytochrome P450 monooxygenase inhibitor wouldbe in an amount effective to inhibit metabolism of the compounds of thepresent invention. Accordingly, the CYP inhibitor is administered in anamount such that the bioavailability of the compounds of the presentinvention is increased in comparison to the bioavailability in theabsence of the CYP inhibitor.

The term “room temperature” used in the specification denotes anytemperature ranging between about 20° C. to about 40° C., except andotherwise it is specifically mentioned in the specification.

Unless mentioned otherwise, abbreviations used in description hereinbelow have following meaning:

EDCI means 1-ethyl-3-(3-dimethylaminopropyl)-dicarbodiimide; HATU means2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate; DIPEA means diisopropyl ethylamine; Boc meansbutoxycarbonyl; DMF means dimethylformamide; DMSO meansdimethylsulfoxide; NBS means N-bromosuccinimide; NCS meansN-chlorosuccinimide; NIS means N-iodosuccinimide; EtOAc means ethylacetate; THF means tetrahydrofuran; Tf means triflate; DCM meansdichloromethane; Et₃N means triethylamine; MeOH means methanol; ACNmeans acetonitrile; Ts means tosyl, Ms means mesyl, RT means roomtemperature; Ac means acetyl; HPLC means high performance liquidchromatography, TLC means thin layer chromatography, PEG meanspolyethylene glycol; TFA means trifluoroacetic acid; KF means potassiumfluoride; and DDQ means 2,3-dichloro-5,6-dicyanobenzoquinone.

The following examples are provided to further illustrate the presentinvention and therefore should not be construed in any way to limit thescope of the present invention. All ¹HNMR spectra were obtained in thesolvents indicated and chemical shifts are reported in δ units downfieldfrom the internal standard tetramethylsilane (TMS) and interprotoncoupling constants are reported in Hertz (Hz). In the case of mixture ofisomers, the peak values given are for the dominant isomer(rotamer/tautomer).

Example 1 Synthesis ofdimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,9b-dihydro-3aH-thieno[3,2-c]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 1) Step 1: 7-bromo-4-chloro-2H-chromene-3-carbaldehyde (1a)

Anhydrous dimethylformamide (8.18 ml, 106 mmol) was taken in atwo-necked round bottomed flask fitted with a dropping funnel. POC₃(7.23 ml, 78 mmol) was added to it by keeping the flask in an ice bathand after the completion of addition, the ice bath was removed and themixture was stirred at RT for 1 hr. 7-bromochroman-4-one (16 g, 71 mmol)was dissolved in 200 ml of chloroform and was slowly added to the flaskkept on an ice bath, and after completion of the addition, the ice bathwas removed and the reaction mixture was stirred overnight at 60° C. Thereaction was brought to RT and ice cold water was added to it and thecompound was extracted with chloroform. The organic layer was washedwith 10% NaHCO₃ solution and dried over Na₂SO₄, filtered andconcentrated to obtain the crude title compound (15.1 g, 78%) which wassufficiently pure enough for the next step. m/z 273.9 (M⁺)

¹H-NMR (400 MHz, CDCl₃): δ 10.16 (s, 1H), 7.55 (d, J=8 Hz, 1H),7.23-7.20 (m, 1H), 7.12-7.11 (m, 1H), 5.03 (s, 2H).

Step 2: 1-(7-bromo-4H-thieno[3,2-c]chromen-2-yl)ethanone (1b)

To a solution of sodium methoxide (5.57 g, 103 mmol) in 250 ml ofmethanol at 0° C., mercaptoacetone (5.11 g, 57 mmol) was addedportion-wise, and after 15 min.,7-bromo-4-chloro-2H-chromene-3-carbaldehyde (1a) (14 g, 52 mmol) wasadded to it portion-wise with stirring. After the addition, the ice bathwas removed and the product gradually started precipitating out as ayellow solid. Stirring was continued for another 3 h, after which waterwas added to quench the reaction and the methanol was removed undervacuum. Addition of more water yielded the title compound as a yellowsolid (1b) which was filtered and dried (14.1 g, 78%). m/z 308.9 (⁷⁹Br)& 310.9 (⁸¹Br).

¹H-NMR (400 MHz, CDCl₃): δ 7.41 (s, 1H), 7.25-7.22 (m, 1H), 7.13-7.11(m, 2H), 5.27 (s, 2H), 2.56 (s, 3H).

Step 3: 1,1′-(4H-thieno[3,2-c]chromene-2,7-diyl)diethanone (1c)

A solution of 1-(7-bromo-4H-thieno[3,2-c]chromen-2-yl)ethanone (1b) (14g, 45.3 mmol) in 300 ml of anhydrous dioxane was degassed by passingnitrogen gas for 45 min. Tributyl(1-ethoxyvinyl)stannane (16.35 g, 45.3mmol) was added to it followed by Pd(PPh₃)₄ (4.19 g, 3.62 mmol) andPdCl₂(dppf)-CH₂Cl₂ adduct (2.65 g, 3.62 mmol) and the solution washeated at 90 OC for overnight. After cooling, the volume of dioxane wasreduced, and a saturated solution of KF was added to it and stirred for15 min., after which the mixture was passed through a pad of celite andwashed with ethyl acetate. The combined filtrate was stirred with 4N HClsolution for 1 h and the organic layer was dried over Na₂SO₄, filteredand concentrated. The residue was purified by column chromatography toobtain the diacetyl compound (1c) (11.5 g, 68%). m/z 272.9 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 7.60-7.58 (m, 1H), 7.54-7.53 (m, 1H),7.47-7.45 (m, 2H), 5.33 (s, 2H), 2.60 (s, 3H), 2.58 (s, 3H).

Step 4: Synthesis of1,1′-(4H-thieno[3,2-c]chromene-2,7-diyl)bis(2-bromoethanone) (1d)

To a solution of 1,1′-(4H-thieno[3,2-c]chromene-2,7-diyl)diethanone (1c)(7 g, 25.7 mmol) in 100 ml of DCM at 0° C., bromine (3.97 ml, 77 mmol)was added dropwise and stirred at room temperature for 2 hr. Thereaction mixture was then added to ice cold water and the DCM layer waspartitioned. The DCM layer was then washed with saturated sodiumbicarbonate solution and saturated brine solution, respectively. Theorganic layer was dried over anhydrous sodium sulphate, filtered andconcentrated under reduced pressure to afford1,1′-(4H-thieno[3,2-c]chromene-2,7-diyl)bis(2-bromoethanone) (12 g, 79%)as a brown solid (1d).

¹H-NMR (400 MHz, CDCl₃): δ 7.98 (s, 1H), 7.72-7.56 (m, 3H), 5.43-5.40(m, 2H), 4.97 (s, 2H), 4.82 (s, 2H).

Step 5:(S)-2-(2-(7-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)oxy)acetyl)-4H-thieno[3,2-c]chromen-2-yl)-2-oxoethyl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (1e)

To a solution of (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylicacid (1d) (8.81 g, 40.9 mmol) in 40 ml of acetonitrile at roomtemperature, Hunig's base (12.96 ml, 74.4 mmol) followed by1,1′-(4H-thieno[3,2-c]chromene-2,7-diyl)bis(2-bromoethanone) (8 g, 18.60mmol) were added and stirred at 50° C. for 4 hr. The volume of solventwas reduced and ethyl acetate was added to the remaining organic layer,which was then washed with water and brine solution. The organic layerwas dried over anhydrous sodium sulphate and concentrated under reducedpressure to afford the product (7 g, 54%) as sticky oil (1e).

¹H-NMR (400 MHz, CDCl₃): δ 7.53-7.42 (m, 4H), 5.40-5.15 (m, 2H),4.44-4.15 (m, 4H), 3.72-3.30 (m, 6H), 2.35-2.20 (m, 4H), 2.10-1.85 (m,4H), 1.45 (s, 9H), 1.35 (s, 9H).

Step 6: (2S,2′S)-di-tert-butyl2,2′-(5,5′-(4H-thieno[3,2-c]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-1-carboxylate)(1f)

To a solution of(S)-2-(2-(7-(2-(((S)-1-(tert-butoxycarbonyflpyrrolidine-2-carbonyl)oxy)acetyl)-4H-thieno[3,2-c]chromen-2-yl)-2-oxoethyl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (1e) (10 g, 14.31 mmol) in500 ml of toluene, ammonium acetate (22.06 g, 286 mmol) was added andthe mixture was refluxed overnight. Toluene was removed under vacuum andethyl acetate was added to dissolve the reaction mixture. The ethylacetate layer was washed with water and brine, dried over anhydroussodium sulphate and concentrated under reduced pressure to afford thecrude product, which was then purified by column chromatography toafford the pure compound (1f) (6 g, 64%). m/z 659.3 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 7.23-7.02 (m, 5H), 6.85-6.80 (m, 1H), 5.23(s, 2H), 5.01-4.97 (m, 2H), 3.52-3.43 (m, 4H), 2.30-1.90 (m, 8H), 1.50(s, 18H).

Step 7:dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4H-thieno[3,2-c]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 1)

To a solution of (2S,2′S)-di-tert-butyl2,2′-(5,5′-(4H-thieno[3,2-c]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-1-carboxylate)(1f) (3 g, 4.55 mmol) in 50 ml of DCM, 10 ml of trifluoroacetic acid wasadded at room temperature and the solution was stirred for 4 hr. Thevolatiles were removed under vacuum and the solid obtained was washedwith diethyl ether and filtered to obtain the TFA salt of thedeprotected compound. To the TFA salt in 10 ml of anhydrous DMF at 0°C., DIPEA (3.98 ml, 22.77 mmol) was added and the contents were stirredfor 10 min. after which (S)-2-((methoxycarbonyflamino)-3-methylbutanoicacid (1.84 g, 10.47 mmol) and HATU (4.33 g, 11.38 mmol) were added andthe reaction mixture was warmed to room temperature and stirredovernight under nitrogen atmosphere. Crushed ice was added to thereaction mixture and the precipitate formed was filtered, the solid waswashed with water, n-pentane and dried and then purified on a Combiflashcolumn with EtOAc-MeOH as eluent to obtain a pale yellow solid (2.28 g,65%). m/z 773.6 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ 8.13 (s, 1H), 7.95 (s, 1H), 7.58-7.55 (m,3H), 7.45-7.43 (m, 1H), 7.30-7.28 (d, J=8 Hz, 2H), 5.38 (s, 2H),5.18-5.11 (m, 2H), 4.13-4.09 (m, 2H), 3.98-3.96 (m, 2H), 3.82-3.65 (m,2H), 3.53 (s, 6H), 2.37-2.33 (m, 2H), 2.17-1.98 (m, 8H), 0.91-0.82 (m,6H), 0.77-0.75 (m, 6H).

Example 2 Synthesis ofdimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 2) Step 1:8-bromo-5-chloro-2,3-dihydrobenzo[b]oxepine-4-carbaldehyde (2a)

was synthesized from 8-bromo-3,4-dihydrobenzo[b]oxepin-5(2H)-one byfollowing an analogous procedure described in Step 1, Example 1. m/z288.2 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 10.35 (s, 1H), 7.62 (d, J=8 Hz, 1H),7.41-7.38 (m, 1H), 7.31 (d, J=2 Hz, 1H), 4.52 (t, J=6 Hz, 2H), 2.62 (t,J=6 Hz, 2H).

Step 2: 1-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)ethanone(2b)

was synthesized from8-bromo-5-chloro-2,3-dihydrobenzo[b]oxepine-4-carbaldehyde (2a) byfollowing an analogous procedure described in Step 2, Example 1. m/z322.9 (⁷⁹Br) & 324.9 (⁸¹Br).

¹H-NMR (400 MHz, CDCl₃): δ 7.62 (d, J=8 Hz, 1H), 7.48 (s, 1H), 7.24-7.23(m, 1H), 7.21-7.19 (m, 1H), 4.35 (t, J=5 Hz, 2H), 3.24 (t, J=5 Hz, 2H),2.55 (s, 3H).

Step 3:1,1′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)diethanone (2c)

was synthesized from1-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)ethanone andTributyl(1-ethoxyvinyl)stannane (2b) by following an analogous proceduredescribed in Step 3, Example 1. m/z 287.0 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ 7.85 (d, J=8 Hz, 1H), 7.66-7.62 (m, 2H), 7.52(s, 1H), 4.38 (t, J=5 Hz, 2H), 3.30 (t, J=5 Hz, 2H), 2.61 (s, 3H), 2.58(s, 3H).

Step 4:1,1′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(2,2-dibromoethanone)(2d)

was synthesized from1,1′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)diethanone (2c)by following an analogous procedure described in Step 4, Example 1.

¹H-NMR (400 MHz, CDCl₃): δ 7.91-7.78 (m, 3H), 7.67-7.65 (m, 1H), 6.64(s, 1H), 6.43 (s, 1H), 4.45-4.41 (m, 2H), 3.36-3.33 (m, 2H).

Step 5:1,1′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(2-bromoethanone)(2e)

To a stirred solution of1,1′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(2,2-dibromoethanone)(2d) (0.65 g, 1.08 mmol) in 20 ml THF at 0° C. was added Et₃N (0.45 ml,3.24 mmol) and diethyl phosphite (0.42 ml, 3.24 mmol). The reactionmixture was gradually warmed to room temperature and the mixture wasstirred for 1 hr. The volatiles were removed under reduced pressure andthe crude residue was washed with n-pentane to yield an yellow solid(2e) that was used in the next step without purification (0.42 g, 88%).

¹H-NMR (400 MHz, CDCl₃): δ 7.90-7.64 (m, 4H), 4.43 (s, 2H), 4.35 (s,2H), 4.30-4.10 (m, 2H), 3.36-3.33 (m, 2H).

Step 6:(S)-2-(2-(8-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)oxy)acetyl)-4,5-dihydrobenzo[b]thieno[2,3-c]oxepin-2-yl)-2-oxoethyl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (2f)

was synthesized from1,1′-(4,5-dihydrobenzo[b]thieno[2,3-c]oxepine-2,8-diyl)bis(2-bromoethanone)and (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (2e) byfollowing an analogous procedure described in Step 5, Example 1.

¹H-NMR (400 MHz, CDCl₃): δ 7.84-7.82 (m, 1H), 7.65-7.50 (m, 3H),5.39-5.13 (m, 4H), 4.50-4.10 (m, 4H), 3.60-3.25 (m, 6H), 2.40-1.91 (m,8H), 1.50 (s, 9H), 1.45 (s, 9H).

Step 7: (2S,2′S)-di-tert-butyl2,2′-(5,5′-(4,5-dihydrobenzo[b]thieno[2,3-c]oxepine-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-1-carboxylate)(2g)

was synthesized from(S)-2-(2-(8-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)oxy)acetyl)-4,5-dihydrobenzo[b]thieno[2,3-c]oxepin-2-yl)-2-oxoethyl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (2f) by following ananalogous procedure described in Step 6, Example 1. m/z 673.3 (M+H)⁺

¹H-NMR (400 MHz, DMSO-d₆): δ 12.00-11.92 (m, 2H), 7.56-7.52 (m, 2H),7.44-7.28 (m, 3H), 7.08 (s, 1H), 4.81-4.73 (m, 2H), 4.27-4.24 (m, 2H),3.52-3.50 (m, 2H), 3.40-3.35 (m, 2H), 3.16-3.15 (m, 2H), 2.30-1.65 (m,8H), 1.33 (s, 9H), 1.17 (s, 9H).

Step 8:dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 2)

was synthesized from (2S,2′S)-di-tert-butyl2,2′-(5,5′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-1-carboxylate)and (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid by following ananalogous procedure described in Step 7, Example 1. m/z 394.3 (M+2H)⁺².

¹H-NMR (400 MHz, DMSO-d₆): δ 12.10-11.84 (m, 2H), 7.52-7.49 (m, 2H),7.40-7.34 (m, 4H), 7.05 (s, 2H), 5.06-5.01 (m, 2H), 4.30-4.26 (m, 2H),4.06-4.02 (m, 2H), 3.85-3.79 (m, 4H), 3.55 (s, 6H), 3.15-3.10 (m, 2H),2.20-1.90 (m, 10H), 0.83-0.81 (m, 12H).

Example 3 Synthesis ofdimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(4-chloro-1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 3)

To a stirred solution ofdimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 2) (0.17 g, 0.216 mmol) in 10 ml DMF, NCS (0.063 g, 0.475mmol) was added and the reaction mixture was stirred for 2 h at 40° C.The progress of the reaction was monitored by TLC. After completereaction of the starting material, the reaction mixture was poured intowater, and the aqueous layer was extracted with ethyl acetate, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudematerial was purified by preparative HPLC to obtain the desired product.m/z 855.4 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ 7.71-7.67 (m, 1H), 7.47-7.45 (m, 1H),7.42-7.40 (m, 1H), 7.33-7.31 (m, 2H), 7.25 (s, 1H), 4.98-4.94 (m, 2H),4.33-4.31 (m, 2H), 4.06-4.02 (m, 2H), 3.79-3.77 (m, 4H), 3.53 (s, 6H),3.24-3.21 (m, 2H), 2.15-1.90 (m, 10H), 0.88-0.82 (m, 12H).

Example 4 Synthesis ofdimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(naphtho[1,2-d]thiazole-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 4) Step 1: 7-bromo-4,5-dihydronaphtho[1,2-d]thiazol-2-amine(4a)

6-bromo-3,4-dihydronaphthalen-1(2H)-one (3.5 g, 15.55 mmol), thiourea(3.55 g, 46.6 mmol) and iodine (4.34 g, 17.10 mmol) were dissolved in 20ml of ethanol and the solution was heated at 100° C. for 4 hr. Thevolume of ethanol was reduced and the solid amine hydroiodide salt wasfiltered and washed with ether. The solid obtained was dissolved inwater and basified with 10% NaOH solution and extracted with ethylacetate. The ethyl acetate layer was dried over Na₂SO₄ and concentratedto obtain the desired compound (4a) (4.37 g, 80%). m/z 280.9 (⁷⁹Br) &282.9 (⁸¹Br) (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 7.54 (d, J=8.4 Hz, 1H), 7.37 (dd, J=2 Hz, 8.4Hz, 1H), 7.32 (d, J=2 Hz, 1H), 5.05 (br s, 2H), 3.03-2.99 (m, 2H),2.88-2.83 (m, 2H).

Step 2: 2,7-dibromo-4,5-dihydronaphtho[1,2-d]thiazole (4b)

To a solution of 7-bromo-4,5-dihydronaphtho[1,2-d]thiazol-2-amine (4a)(1.4 g, 4.98 mmol) in 25 ml of acetonitrile, tert-butyl nitrite (0.724ml, 5.48 mmol) and copper(I) bromide (0.786 g, 5.48 mmol) were added andthe resulting black solution was stirred at 50° C. for 30 min. Thevolume of acetonitrile was reduced under vacuum and water was added toit. The organic material was extracted with ethyl acetate and theorganic layer was dried and concentrated to obtain a brown solid (4b)(1.7 g, 99%). m/z 345.7 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 7.74 (d, J=8.4 Hz, 1H), 7.42 (dd, J=2 Hz, 8.4Hz, 1H), 7.36 (d, J=2 Hz, 1H), 3.06-3.02 (m, 2H), 3.00-2.95 (m, 2H).

Step 3: 1,1′-(4,5-dihydronaphtho[1,2-d]thiazole-2,7-diyl)diethanone (4c)

A solution of 2,7-dibromo-4,5-dihydronaphtho[1,2-d]thiazole (4b) (1.7 g,5.07 mmol) in 30 ml of anhydrous dioxane was degassed by passingnitrogen gas for 15 min. Tributyl(1-ethoxyvinyl)stannane (4.58 g, 12.68mmol) was added to it followed by PdCl₂(PPh₃)₂ (0.36 g, 0.51 mmol) andthe solution was heated at 90° C. overnight. After cooling, the volumeof dioxane was reduced and a saturated solution of KF was added to itand stirred for 15 min., after which the mixture was passed through apad of celite and washed with ethyl acetate. The combined filtrate wasstirred with 4 N HCl solution for 1 h and the organic layer was driedand concentrated and the residue was purified by column chromatographyto obtain the diacetyl compound (4c) (1.37 g, 73%). m/z 271.0 (M⁺).

¹H-NMR (400 MHz, CDCl₃), δ 8.09 (d, J=8 Hz, 1H), 7.94 (dd, J=1.6 Hz, 8Hz, 1H), 7.87 (d, J=1.6 Hz, 1H), 3.20-3.15 (m, 4H), 2.78 (s, 3H), 2.65(s, 3H).

Step 4: 1,1′-(naphtho[1,2-d]thiazole-2,7-diyl)bis(2-bromoethanone) (4d)

was synthesized from1,1′-(4,5-dihydronaphtho[1,2-d]thiazole-2,7-diyl)diethanone (4c) byfollowing an analogous procedure described in Step 4, Example 1.

¹H-NMR (400 MHz, DMSO-d₆): δ 8.85-8.82 (m, 1H), 8.40-8.26 (m, 3H), 7.95(s, 1H), 5.21 (s, 2H), 5.11 (s, 2H).

Step 5: (2S,2′S)-di-tert-butyl2,2′-(5,5′-(naphtho[1,2-d]thiazole-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-1-carboxylate)(4e)

was synthesized from1,1′-(naphtho[1,2-d]thiazole-2,7-diyl)bis(2-bromoethanone) (4d) and(5)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid by following ananalogous procedure described in Step 5 of Example 1 followed by Step 6,Example 1. m/z 656.1 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 8.75-8.72 (m, 1H), 8.47 (s, 1H), 8.22-8.19(m, 1H), 8.01-7.86 (m, 3H), 7.43 (s, 1H), 5.18-5.16 (m, 2H), 4.38-4.35(m, 2H), 3.69-3.50 (m, 2H), 3.40-3.37 (m, 2H), 2.27-2.19 (m, 2H),2.06-1.90 (m, 4H), 1.54 (s, 9H), 1.51 (s, 9H).

Step 6:dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(naphtho[1,2-d]thiazole-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 4)

was synthesized from (2S,2′S)-di-tert-butyl2,2′-(5,5′-(naphtho[1,2-d]thiazole-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-1-carboxylate)(4e) by following an analogous procedure described in Step 7, Example 1.m/z 770.2 (M+H)⁺.

¹H-NMR (400 MHz, CD₃OD): δ 8.72 (d, J=8.8 Hz, 1H), 8.34-8.26 (m, 1H),7.98-7.96 (m, 2H), 7.86-7.80 (m, 2H), 7.47 (s, 1H), 5.22-5.20 (m, 2H),4.27-4.25 (m, 2H), 4.05-3.99 (m, 2H), 3.94-3.92 (m, 2H), 3.67 (s, 6H),3.48-3.45 (m, 2H), 2.40-2.22 (m, 4H), 2.16-2.01 (m, 4H), 1.03-0.91 (m,12H).

Example 5 Synthesis ofdimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 5) Step 1: 1-chloro-3,4-dihydronaphthalene-2-carbaldehyde (5a)

was synthesized from α-tetralone by following an analogous proceduredescribed in Step 1, Example 1. m/z 193.0 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 10.41 (s, 1H), 7.89-7.87 (m, 1H), 7.41-7.33(m, 2H), 7.24-7.22 (m, 1H), 2.90-2.84 (m, 2H), 2.67-2.63 (m, 2H).

Step 2: 1-(4,5-dihydronaphtho[1,2-b]thiophen-2-yl)ethanone (5b)

was synthesized from 1-chloro-3,4-dihydronaphthalene-2-carbaldehyde (5a)by following an analogous procedure described in Step 2, Example 1. m/z227.9 (M⁺).

¹H-NMR (400 MHz, CDCl₃): δ 7.52 (s, 1H), 7.49-7.46 (m, 1H), 7.29-7.24(m, 3H), 3.10-2.97 (m, 2H), 2.88-2.84 (m, 2H), 2.57 (s, 3H).

Step 3: 1,1′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)diethanone(5c)

To a solution of 1-(4,5-dihydronaphtho[1,2-b]thiophen-2-yl)ethanone (5b)(30 g, 131 mmol) in 500 mL of DCM at 0° C., AlCl₃ (52.6 g, 394 mmol) wasadded portion wise and after 15 min, acetyl chloride (18.69 ml, 263mmol) was added dropwise at the same temperature over 30 min and themixture was stirred at room temperature for 48 hr. The reaction mass wasslowly added to ice water and acidified with 2 N HCl solution andextracted with DCM, and the organic layer was dried over anhydroussodium sulphate and concentrated under reduced pressure to afford thetitle compound as an yellow solid (5c) (28.3 g, 80%). m/z 270.0 (M⁺).

¹H-NMR (400 MHz, CDCl₃): δ 7.86-7.83 (m, 2H), 7.54-7.52 (m, 2H),3.07-3.04 (m, 2H), 2.93-2.89 (m, 2H), 2.62 (s, 3H), 2.58 (s, 3H).

Step 4:1,1′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(2,2-dibromoethanone)(5d)

was synthesized from1,1′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)diethanone (5c) byfollowing an analogous procedure described in Step 4, Example 1.

¹H-NMR (400 MHz, DMSO-d₆): δ 8.15-7.97 (m, 2H), 7.90-7.87 (m, 2H),7.68-7.62 (m, 2H), 3.06-3.02 (m, 2H), 2.90-2.88 (m, 2H).

Step 5:1,1′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(2-bromoethanone)(5e)

was synthesized from1,1′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(2,2-dibromoethanone)(5d) by following an analogous procedure described in Step 5, Example 2.

¹H-NMR (400 MHz, CDCl₃): δ 7.89-7.87 (m, 2H), 7.58-7.53 (m, 2H), 4.45(s, 2H), 4.36 (m, 2H), 3.87-3.78 (m, 2H), 3.75-3.70 (m, 2H).

Step 6:(S)-2-(2-(7-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)oxy)acetyl)-4,5-dihydronaphtho[1,2-b]thiophen-2-yl)-2-oxoethyl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (5f)

was synthesized from1,1′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(2-bromoethanone)and (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic (5e) acid byfollowing an analogous procedure described in Step 5, Example 1.

¹H-NMR (400 MHz, CDCl₃): δ 7.79-7.77 (m, 2H), 7.59-7.52 (m, 2H),5.39-5.25 (m, 4H), 4.41-4.20 (m, 4H), 3.60-3.30 (m, 4H), 3.10-2.90 (m,2H), 2.40-2.20 (m, 4H), 2.10-1.85 (m, 4H), 1.47-1.40 (m, 18H).

Step 7: (2S,2′S)-di-tert-butyl2,2′-(5,5′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-1-carboxylate)(5g)

was synthesized from(S)-2-(2-(7-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)oxy)acetyl)-4,5-dihydronaphtho[1,2-b]thiophen-2-yl)-2-oxoethyl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (50 by following an analogousprocedure described in Step 6, Example 1. m/z 657.4 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ 7.61-7.50 (m, 2H), 7.32-7.30 (m, 1H),7.21-7.13 (m, 2H), 7.10-7.01 (m, 1H), 4.98-4.95 (m, 2H), 3.56-3.33 (m,4H), 2.98-2.80 (m, 4H), 2.26-1.92 (m, 8H), 1.51 (s, 18H).

Step 8:dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamatedihydrochloride salt (dihydrochloride salt of Compound 5)

was synthesized from ((2S,2′S)-di-tert-butyl2,2′-(5,5′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-1-carboxylate)(5g) and (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid byfollowing an analogous procedure described in Step 7, Example 1. Thefree base was dissolved in MeOH and a 3 N HCl solution in MeOH was addedto it and the resulting solution was stirred for 30 min., after whichthe volume of MeOH was reduced and acetone was added to precipitate outa pale yellow solid, which was washed with diethyl ether and dried toobtain the dihydrochloride salt of the title compound. m/z 771.4 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ 8.14-8.10 (m, 1H), 7.95-7.91 (m, 1H),7.80-7.73 (m, 2H), 7.65-7.52 (m, 1H), 7.46-7.44 (d, J=8 Hz, 1H),7.36-7.34 (d, J=8 Hz, 2H), 5.15-5.10 (m, 2H), 4.11-4.10 (m, 2H),3.91-3.85 (m, 4H), 3.54 (s, 6H), 3.00-2.89 (m, 2H), 2.87-2.85 (m, 2H),2.39-2.01 (m, 8H), 0.90-0.76 (m, 12H).

Example 6 Synthesis ofdimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(3-chloro-4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(4-chloro-1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 6)

was synthesized fromdimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate,(Compound 5) by following an analogous procedure described in Example 3.m/z 875.2 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ 12.60-12.50 (m, 2H), 7.68-7.60 (m, 2H),7.50-7.48 (m, 1H), 7.40-7.30 (m, 2H), 5.05-4.95 (m, 2H), 4.11-4.00 (m,2H), 3.85-3.70 (m, 4H), 3.54 (s, 6H), 3.10-3.00 (m, 2H), 2.90-2.80 (m,2H), 2.20-1.85 (m, 10H), 0.90-0.76 (m, 12H).

Example 7 Synthesis ofdimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 7) Step 1: ((2S,2′S)-di-tert-butyl2,2′-(5,5′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-1-carboxylate)(7a)

To a stirred solution of (2S,2′S)-di-tert-butyl2,2′-(5,5′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-1-carboxylate),(5g) (0.5 g, 0.76 mmol) in 20 ml of toluene, DDQ (0.346 g, 1.52 mmol)was added and the mixture was stirred at 90° C. for 16 hr. The reactionmixture was then concentrated under reduced pressure, and 100 ml ofsaturated sodium bicarbonate solution was added and the organic materialwas extracted with ethyl acetate. The ethyl acetate layer was dried overanhydrous sodium sulphate and concentrated under reduced pressure toobtain the crude compound which was purified by column chromatography toobtain the aromatised compound as an yellow solid (7a) (0.25 g, 51%).m/z 655.5 (M+H)⁺

¹H-NMR (400 MHz, CDCl₃): δ 12.11-12.03 (m, 1H), 11.97-11.90 (m, 1H),8.32 (s, 1H), 8.00 (s, 2H), 7.77 (s, 2H), 7.63-7.55 (m, 3H), 4.87-4.80(m, 2H), 3.56-3.50 (m, 2H), 3.40-3.35 (m, 3H), 2.27-2.20 (m, 3H),2.02-1.87 (m, 4H), 1.41 (s, 9H), 1.18 (s, 9H).

Step 2:dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 7 and its dihydrochloride salt)

was synthesized from ((2S,2′S)-di-tert-butyl2,2′-(5,5′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-1-carboxylate)(7a) by following an analogous procedure described in Step 7, Example 1.The free base was dissolved in MeOH and a 3 N HCl solution in MeOH wasadded to it and the resulting solution was stirred for 30 min., afterwhich the volume of MeOH was reduced and acetone was added toprecipitate out a pale yellow solid, which was washed with diethyl etherand dried to obtain the dihydrochloride salt of the title compound. m/z769.2 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ 15.33 (br s, 1H), 14.77 (br s, 1H), 8.62(s, 1H), 8.25-8.18 (m, 2H), 8.13-8.01 (m, 4H), 7.89-7.87 (m, 1H),7.34-7.32 (m, 2H), 5.21-5.15 (m, 2H), 4.16-4.10 (m, 2H), 3.98-3.85 (m,4H), 3.54 (s, 6H), 2.50-2.38 (m, 2H), 2.20-2.19 (m, 4H), 2.10-2.01 (m,4H), 0.92-0.77 (m, 12H).

Example 8 Synthesis ofdimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 8) Step 1:9-chloro-6,7-dihydro-5H-benzo[7]annulene-8-carbaldehyde (8a)

was synthesized from 6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-one byfollowing an analogous procedure described in Step 1, Example 1. m/z205.9 (M⁺).

¹H-NMR (400 MHz, CDCl₃): δ 10.10 (s, 1H), 7.70-7.66 (m, 1H), 7.41-7.36(m, 2H), 7.29-7.28 (m, 1H), 2.63 (t, J=7 Hz, 2H), 2.26-2.06 (m, 4H).

Step 2:1-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophen-2-yl)ethanone (8b)

was synthesized from9-chloro-6,7-dihydro-5H-benzo[7]annulene-8-carbaldehyde (8a) byfollowing an analogous procedure described in Step 2, Example 1. m/z242.1 (M⁺).

¹H-NMR (400 MHz, CDCl₃): δ 7.56 (s, 1H), 7.52-7.47 (m, 1H), 7.36-7.25(m, 3H), 2.71-2.63 (m, 4H), 2.58 (s, 3H), 2.30-2.19 (m, 2H).

Step 3:1,1′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)diethanone(8c)

was synthesized from1-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophen-2-yl)ethanone (8b)by following an analogous procedure described in Step 3, Example 5. m/z283.9 (M⁺).

¹H-NMR (400 MHz, CDCl₃): δ 8.05-8.02 (m, 1H), 7.90-7.86 (m, 1H),7.57-7.55 (m, 1H), 7.40-7.38 (m, 1H), 2.75-2.68 (m, 4H), 2.64 (s, 3H),2.58 (s, 3H), 2.29-2.26 (m, 2H).

Step 4:1,1′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)bis(2-bromoethanone)(8d)

was synthesized from1,1′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)diethanone(8c) by following an analogous procedure described in Step 4, Example 1.

¹H-NMR (400 MHz, CDCl₃): δ 8.09-8.05 (m, 1H), 7.96-7.90 (m, 1H),7.68-7.59 (m, 1H), 7.57-7.54 (m, 1H), 4.48 (s, 2H), 4.37 (s, 2H),2.78-2.65 (m, 4H), 2.34-2.28 (m, 2H).

Step 5:(S)-2-(2-(8-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)oxy)acetyl)-5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophen-2-yl)-2-oxoethyl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (8e)

was synthesized from1,1′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)bis(2-bromoethanone)and (S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carboxylic acid (8d) byfollowing an analogous procedure described in Step 5, Example 1.

¹H-NMR (400 MHz, CDCl₃): δ 8.06-7.43 (m, 4H), 4.48-4.14 (m, 4H),3.74-3.70 (m, 2H), 3.45-3.33 (m, 2H), 3.16-3.12 (m, 2H), 2.71-2.68 (m,4H), 2.34-2.29 (m, 4H), 2.06-1.90 (m, 6H), 1.48-1.34 (m, 18H).

Step 6: (2S,2′S)-di-tert-butyl2,2′-(5,5′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-1-carboxylate)(8f)

was synthesized from(S)-2-(2-(8-(2-(((S)-1-(tert-butoxycarbonyl)pyrrolidine-2-carbonyl)oxy)acetyl)-5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophen-2-yl)-2-oxoethyl)1-tert-butyl pyrrolidine-1,2-dicarboxylate (8e) by following ananalogous procedure described in Step 6, Example 1. m/z 671.4 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 7.70-7.10 (m, 6H), 5.01-4.98 (m, 2H),3.57-3.36 (m, 4H), 2.90-2.56 (m, 4H), 2.35-1.91 (m, 8H), 1.51-1.40 (m,18H).

Step 7:dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 8)

was synthesized from (2S,2′S)-di-tert-butyl2,2′-(5,5′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-1-carboxylate)(8f) by following an analogous procedure described in Step 7, Example 1.m/z 782.5 (M+H)⁺.

¹H-NMR (400 MHz, CD₃OD): δ 7.78-7.73 (m, 1H), 7.56-7.42 (m, 2H),7.31-7.25 (m, 2H), 7.20-7.16 (m, 1H), 7.10-7.09 (m, 1H), 5.15-5.10 (m,2H), 4.24-4.22 (m, 2H), 4.05-3.87 (m, 4H), 3.66 (s, 6H), 2.75-2.69 (m,4H), 2.35-2.21 (m, 8H), 2.07-2.02 (m, 4H), 1.00-0.90 (m, 12H).

Example 9 Synthesis ofdimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)bis(4-chloro-1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 9)

was synthesized fromdimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 8) by following an analogous procedure described in Example 3.m/z 853.3 (M+H)⁺.

¹H-NMR (400 MHz, CD₃OD): δ 7.78-7.75 (m, 1H), 7.67-7.55 (m, 2H),7.35-7.33 (m, 1H), 7.09-7.06 (m, 2H), 5.07-5.06 (m, 2H), 4.22-4.20 (m,2H), 4.05-3.87 (m, 4H), 3.65 (s, 6H), 2.75-2.69 (m, 4H), 2.35-2.21 (m,8H), 2.07-2.02 (m, 4H), 1.00-0.92 (m, 12H).

Example 10 Synthesis of dimethylU2S,2′S)-((1R,1′R,3S,3'S,4S,4′S)-3,3′-(5,5′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-azabicyclo[2.2.1]heptane-3,2-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 10) Step 1: 1,1′-(naphtho[1,2-b]thiophene-2,7-diyl)diethanone(10a)

To a stirred solution of1,1′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl))diethanone (5c) (1 g,3.7 mmol) in 30 ml of toluene, DDQ (0.84 g, 3.7 mmol) was added and themixture was stirred at 110° C. for 60 hr. The reaction mixture wasconcentrated under reduced pressure, 100 ml water was added and theorganics were extracted with ethyl acetate. The organic layer was driedover anhydrous sodium sulphate and concentrated under reduced pressureto obtain the crude compound which was purified by column chromatographyto obtain 1,1′-(naphtho[1,2-b]thiophene-2,7-diyl)diethanone as a brownsolid (10a) (0.45 g, 55%).

¹H-NMR (400 MHz, CDCl₃): δ 8.55 (s, 1H), 8.24 (d, J=8 Hz, 1H), 8.17 (dd,J=8 Hz, 1 Hz, 1H), 8.01 (s, 1H), 7.92-7.86 (m, 2H), 2.77 (s, 3H), 2.73(s, 3H).

Step 2: 1,1′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(2,2-dibromoethanone)(10b)

To a solution of 1,1′-(naphtho[1,2-b]thiophene-2,7-diyl)diethanone (10a)(100 g, 373 mmol) in 300 ml of DCM, bromine (48 ml, 932 mmol) was addeddrop wise at room temperature. After the addition, the solution wasstirred at room temperature for 3 hr. The reaction mixture wasconcentrated under reduced pressure at 35° C. to obtain a semi-solidmaterial, which was washed with a minimum amount of DCM and filtered toobtain a brown solid. The brown solid was washed with diethyl ether toyield the title compound (10b) (189 g, 88%).

¹H-NMR (400 MHz, CDCl₃): δ 8.74 (s, 1H), 8.42 (s, 1H), 8.28 (s, 2H),8.00-7.80 (m, 2H), 6.83 (s, 1H), 6.61 (s, 1H).

Step 3: 1,1′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(2-bromoethanone)(10c)

1,1′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(2,2-dibromoethanone) (10b)(180 g, 310 mmol) obtained as above was dissolved in 500 ml of THF andthe solution was cooled to 0° C. A mixture of diethyl phosphite (80 ml,620 mmol) and triethylamine (86 ml, 210 mmol) in 50 ml THF was addeddropwise to the solution which was kept on an ice bath. After theaddition, the ice bath was removed and the reaction mixture was stirredat room temperature for 2 hr. The volume of THF was reduced by rotaryevaporation to obtain a solid residue which was washed with pentane toafford 1,1′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(2-bromoethanone) as abrown solid (10c) (110 g, 84%).

¹H-NMR (400 MHz, DMSO-d₆): δ 8.88-8.84 (m, 1H), 8.66 (s, 1H), 8.44-8.38(m, 1H), 8.19-8.09 (m, 3H), 5.11 (s, 2H), 5.03 (s, 2H).

Step 4:(1R,3S,4S)-3-(2-(2-(2-(((1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carbonyl)oxy)acetyl)naphtho[1,2-b]thiophen-7-yl)-2-oxoethyl)2-tert-butyl 2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (10d)

was synthesized from1,1′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(2-bromoethanone) (10c) and(1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylicacid (see, e.g., WO 2012/041227) by following an analogous proceduredescribed in Step 5, Example 1. m/z 746.3 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 8.52-8.50 (m, 1H), 8.27-8.25 (m, 1H),8.15-8.10 (m, 2H), 7.95-7.87 (m, 2H), 5.57-5.31 (m, 4H), 4.41-4.40 (m,1H), 4.29-4.27 (m, 1H), 4.05-4.04 (m, 2H), 3.99-3.97 (m, 2H), 3.07-2.88(m, 2H), 1.80-1.75 (m, 4H), 1.74-1.65 (m, 4H), 1.62-1.57 (m, 2H),1.51-1.44 (m, 18H).

Step 5: (1R,1′R,3S,3'S,4 S,4′S)-di-tert-butyl3,3′-(5,5′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-azabicyclo[2.2.1]heptane-2-carboxylate)(10e)

was synthesized from(1R,3S,4S)-3-(2-(2-(2-(((1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carbonyl)oxy)acetyl)naphtho[1,2-b]thiophen-7-yl)-2-oxoethyl) 2-tert-butyl2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (10d) and ammonium acetateby following an analogous procedure described in Step 6, Example 1. m/z706.1 (M+H)⁺.

Step 6:dimethyl((2S,2′S)-((1R,1′R,3S,3'S,4S,4′S)-3,3′-(5,5′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-azabicyclo[2.2.1]heptane-3,2-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate(Compound 10)

was synthesized from (1R,1′R,3S,3′S,4S,4′S)-di-tert-butyl3,3′-(5,5′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-azabicyclo[2.2.1]heptane-2-carboxylate)and (S)-2-((methoxycarbonyl)-amino)-3-methylbutanoic acid (10e) byfollowing an analogous procedure described in Step 7, Example 1. m/z820.4 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 8.28 (br s, 1H), 7.98-7.97 (m, 2H), 7.77-7.54(m, 5H), 7.21-7.19 (d, J=8 Hz, 2H), 4.54-4.52 (m, 4H), 4.16-4.12 (m,2H), 3.54 (s, 6H), 2.60-2.55 (m, 2H), 2.01-1.99 (m, 2H), 1.86-1.75 (m,6H), 1.56-1.44 (m, 4H), 1.23-1.12 (m, 2H), 1.01-0.94 (m, 6H), 0.90-0.89(m, 6H).

Example 11 Synthesis ofmethyl((S)-1-((S)-2-(5-(2-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonyl)amino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphtho[1,2-b]thiophen-7-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate(Compound 11) Step 1:6-bromo-1-chloro-3,4-dihydronaphthalene-2-carbaldehyde (11a)

was synthesized from 6-bromo-3,4-dihydronaphthalen-1(2H)-one byfollowing an analogous procedure described in Step 1, Example 1.

¹H-NMR (400 MHz, CDCl₃): δ 7.72 (d, J=8 Hz, 1H), 7.48 (dd, J=8 Hz, 2 Hz,1H), 7.39 (s, 1H), 2.84 (t, J=6 Hz, 2H), 2.64 (t, J=6 Hz, 2H).

Step 2: 1-(7-bromo-4,5-dihydronaphtho[1,2-b]thiophen-2-yl) ethanone(11b)

was synthesized from6-bromo-1-chloro-3,4-dihydronaphthalene-2-carbaldehyde (11a) byfollowing an analogous procedure described in Step 2, Example 1. m/z305.9, 307.9.

¹H-NMR (400 MHz, CDCl₃): δ 7.50 (s, 1H), 7.40 (s, 1H), 7.37 (d, J=2 Hz,1H), 7.32 (d, J=8 Hz, 1H), 2.97 (t, J=6 Hz, 2H), 2.85 (t, J=6 Hz, 2H),2.56 (s, 3H).

Step 3: 1-(7-bromonaphtho[1,2-b]thiophen-2-yl)ethanone (11c)

-   1-(7-bromo-4,5-dihydronaphtho[1,2-b]thiophen-2-yl) ethanone (11b)    (600 mg, 1.95 mmol) was dissolved in 20 ml toluene and manganese    dioxide (943 mg, 9.77 mmol) was added and the mixture was heated at    100° C. for 26 hr. Aliquots were taken in between to check the    progress of the reaction by HPLC. Once the reaction was complete,    the mixture was filtered over a pad of celite, and the celite pad    was washed with ethyl acetate. The ethyl acetate layer was    concentrated to obtain the desired compound (11c) (0.51 g, 85%). m/z    304, 306 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 8.09 (d, J=2 Hz, 1H), 8.04 (d, J=8 Hz, 2H),7.83 (d, J=8 Hz, 1H), 7.69 (dd, J=8 Hz, 2 Hz, 1H), 7.66 (d, J=8 Hz, 1H),2.71 (s, 3H).

Step 4: 2-(7-bromonaphtho[1,2-b]thiophen-2-yl)-2-oxoethyl4-methylbenzenesulfonate (11d)

To a solution of 1-(7-bromonaphtho[1,2-b]thiophen-2-yl)ethanone (11c)(1.26 g, 4.13 mmol) in 15 ml of acetonitrile at 75° C.,hydroxytosyloxyiodobenzene (2.59 g, 6.61 mmol) was added and the mixturewas refluxed for 8 hr. The volume of acetonitrile was reduced undervacuum and ethanol was added to it. The orange solid obtained wasfiltered and washed with ether to obtain the desired compound (11d) (1.6g, 82%).

¹H-NMR (400 MHz, DMSO-d₆): δ 8.53 (s, 1H), 8.39 (d, J=8 Hz, 1H), 8.21(d, J=8 Hz, 1H), 8.02 (d, J=8 Hz, 1H), 7.93 (s, 1H), 7.89 (d, J=8 Hz,2H), 7.82 (dd, J=8 Hz & 2 Hz, 1H), 7.50 (d, J=8 Hz, 2H), 5.65 (s, 2H),2.43 (s, 3H).

Step 5: Synthesis of(1R,3S,4S)-3-(2-(7-bromonaphtho[1,2-b]thiophen-2-yl)-2-oxoethyl)2-tert-butyl2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (11e)

The above compound was synthesized from2-(7-bromonaphtho[1,2-b]thiophen-2-yl)-2-oxoethyl4-methylbenzenesulfonate (11d) and(1R,3S,4S)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptane-3-carboxylicacid by following an analogous procedure described in Step 5, Example 1.m/z 543.9, 545.9 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 8.11-8.09 (m, 2H), 8.04-8.01 (m, 1H), 7.85(d, J=8.8 Hz, 1H), 7.72-7.64 (m, 2H), 5.60-5.25 (m, 2H), 4.40-4.27 (m,1H), 4.04-3.96 (m, 1H), 3.02-3.00 (m, 1H), 2.11-2.06 (m, 2H), 1.83-1.58(m, 4H), 1.48-1.46 (m, 9H).

Step 6: (1R,3S,4S)-tert-butyl3-(5-(7-bromonaphtho[1,2-b]thiophen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(11f)

was synthesized from(1R,3S,4S)-3-(2-(7-bromonaphtho[1,2-b]thiophen-2-yl)-2-oxoethyl)2-tert-butyl 2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate (11e) andammonium acetate by following an analogous procedure described in Step6, Example 1. m/z 524.4, 526.4 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 8.04 (m, 1H), 7.94 (d, J=8.8 Hz, 1H), 7.75(d, J=8.8 Hz, 1H), 7.59 (d, J=8.8 Hz, 2H), 7.30 (s, 1H), 4.46 (s, 1H),4.18 (s, 1H), 3.47 (s, 1H), 2.06-1.62 (m, 6H), 1.55-1.52 (m, 9H).

Step 7: (1R,3S,4S)-tert-butyl3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphtho[1,2-b]thiophen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(11g)

Dioxane (10 ml) was degassed by passing nitrogen for 15 min. and amixture of bis-pinacolatodiboron (261 mg, 1.03 mmol), potassium acetate(152 mg, 1.55 mmol), tricyclohexylphosphine (11.55 mg, 0.04 mmol),PdCl₂(dppf)-CH₂Cl₂— adduct (33.6 mg, 0.04 mmol) and(1R,3S,4S)-tert-butyl3-(5-(7-bromonaphtho[1,2-b]thiophen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(11f) (270 mg, 0.52 mmol) was added in a microwave vial and the cap wassealed. The mixture was heated at 95° C. for 8 hr. The reaction mixturewas diluted with ethyl acetate and the ethyl acetate layer was washedwith water, dried and concentrated to obtain the crude compound whichwas purified on a Combiflash column to obtain the title compound (11g)(0.27 g, 92%). m/z 571.8 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 8.42 (s, 1H), 8.06 (d, J=8 Hz, 1H), 7.93 (d,J=8 Hz, 1H), 7.75 (s, 2H), 7.64 (s, 1H), 7.31 (s, 1H), 4.46 (s, 1H),4.18 (s, 1H), 3.54 (s, 1H), 2.06-1.61 (m, 6H), 1.42 (s, 12H), 1.27-1.24(m, 9H).

Step 8: (1R,3S,4S)-tert-butyl3-(5-(7-(2-((S)-1-(tert-butoxycarbonyflpyrrolidin-2-yl)-1H-imidazol-5-yl)naphtho[1,2-b]thiophen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(11 h)

A mixture of 6 ml of toluene and 2 ml of water was purged with nitrogenand (1R,3S,4S)-tert-butyl3-(5-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphtho[1,2-b]thiophen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(11h) (300 mg, 0.53 mmol), (S)-tert-butyl2-(5-iodo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (286 mg, 0.79mmol), (see, e.g., WO 2010096302), K₃PO₄ (334 mg, 1.58 mmol), Pd(PPh₃)₄(61 mg, 0.05 mmol) and tricyclohexylphosphine (15 mg, 0.05 mmol) wereadded in a reaction vessel and sealed. The reaction vessel was heated inan oil bath at 100° C. for 24 hr. After completion of the reaction, thecompound formed was extracted into ethyl acetate, and the ethyl acetatelayer was washed with water, dried over Na₂SO₄ and concentrated. Thecrude material was purified on a Combiflash column to obtain the titlecompound (11h) (0.16 g, 45%). m/z 681.2 (M+H)⁺.

¹H-NMR (400 MHz, CDCl₃): δ 7.81 (s, 1H), 7.70-7.66 (m, 2H), 7.61-7.54(m, 2H), 7.51-7.46 (m, 2H), 7.07 (s, 1H), 5.13 (br s, 2H), 4.50 (m, 2H),3.51 (m, 3H), 2.22-1.75 (m, 6H), 1.55-1.49 (m, 18H), 1.34-1.30 (m, 3H).

Step 9: Synthesis ofmethyl((S)-1-((S)-2-(5-(2-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonyl)amino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphtho[1,2-b]thiophen-7-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamatedihydrochloride salt (Compound 11)

The above compound was synthesized from (1R,3S,4S)-tert-butyl3-(5-(7-(2-((S)-1-(tert-butoxycarbonyflpyrrolidin-2-yl)-1H-imidazol-5-yl)naphtho[1,2-b]thiophen-2-yl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate(11h) and (S)-2-((methoxycarbonyl)-amino)-3-methylbutanoic acid byfollowing an analogous procedure described in Step 7, Example 1. m/z795.2 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ 15.26 (br s, 1H), 14.74 (br s, 1H), 8.58(s, 1H), 8.22-8.19 (m, 2H), 8.09 (d, J=8 Hz, 1H), 8.01 (d, J=8 Hz, 1H),7.86 (d, J=8 Hz, 1H), 7.35-7.33 (m, 2H), 5.20-5.18 (m, 2H), 4.72-4.48(m, 2H), 4.22-4.11 (m, 2H), 3.96-3.86 (m, 2H), 3.56 (s, 3H), 3.54 (s,3H), 2.72-2.70 (m, 2H), 2.19-2.05 (m, 4H), 1.85-1.71 (m, 4H), 1.52-1.49(m, 2H), 0.96-0.76 (m, 12H).

Example 12 Biological Activity

Anti-viral activity of the compounds of the invention was monitoredusing an HCV replicon assay. The Huh7.5 Con1/SG-Neo(I)hRluc2aUb cellline persistently expressing a bicistronic genotype 1b replicon in Huh7.5 cells and the Huh7.5/J6/JFH1/EMCVIRES/hRlucNeo cell line expressinga bicistronic genotype 2a replicon in Huh 7.5 cells were obtained fromApath LLC. These cell lines were used to test inhibition of repliconlevels by test compound using Renilla luciferase enzyme activity readoutas a measure of viral replication efficiency.

Briefly, 7000-7500 cells were seeded in 96 well black clear bottomplates and allowed to adhere overnight. The next day each compound wasadded in triplicate to the cells at the desired concentration with afinal DMSO concentration of 0.5%. Cells in media alone and cellsincubated without drug with 0.5% DMSO served as controls. The plateswere incubated for 72h at 37° C. prior to running the luciferase assay.Enzyme activity was measured using Renilla-Glo Luciferase Assay kit fromPromega as per the manufacturer's instructions. The following equationwas used to generate the percent inhibition value for each testconcentration.

${\% \mspace{14mu} {Inhibition}} = {\frac{\begin{matrix}{{{Average}\mspace{14mu} {Control}\; \left( {{{cells}\mspace{14mu} {alone}} + {0.5\% \mspace{14mu} {DMSO}}} \right)} -} \\{{Average}\mspace{14mu} {compound}\mspace{14mu} {{value}\left( {{cells} + {drug}} \right)}}\end{matrix}}{{Average}\mspace{14mu} {Control}\; \left( {{{cells}\mspace{14mu} {alone}} + {0.5\% \mspace{14mu} {DMSO}}} \right)} \times 100}$

The IC₅₀ value was determined using GraphPad Prism and the followingequation:

Y=Bottom+(Top−Bottom)(1+10̂((LogIC₅₀ −X)*Hill slope))

IC₅₀/values % inhibitions of compounds were determined 2-3 times in thereplicon assays.

Table 1 sets forth the IC₅₀ values, for inhibition of genotype 1b and 2areplicons, of the compounds in accordance with an embodiment of theinvention. Group A compounds exhibited 1050 value between 1 pM to 999pM, Group B exhibited IC₅₀ value between 1 nM to 100 nM, and Group Cexhibited IC₅₀ value of more than 100 nM.

TABLE 1 Compound No Gt1b IC₅₀ Gt2a IC₅₀ 1 A A 2 A B 3 A B 4 A C 5 A A 6A A 7 A A 8 A A 9 A A 10 A A 11 A A

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and “at least one” andsimilar referents in the context of describing the invention (especiallyin the context of the following claims) are to be construed to coverboth the singular and the plural, unless otherwise indicated herein orclearly contradicted by context. The use of the term “at least one”followed by a list of one or more items (for example, “at least one of Aand B”) is to be construed to mean one item selected from the listeditems (A or B) or any combination of two or more of the listed items (Aand B), unless otherwise indicated herein or clearly contradicted bycontext. The terms “comprising,” “having,” “including,” and “containing”are to be construed as open-ended terms (i.e., meaning “including, butnot limited to,”) unless otherwise noted. Recitation of ranges of valuesherein are merely intended to serve as a shorthand method of referringindividually to each separate value falling within the range, unlessotherwise indicated herein, and each separate value is incorporated intothe specification as if it were individually recited herein. All methodsdescribed herein can be performed in any suitable order unless otherwiseindicated herein or otherwise clearly contradicted by context. The useof any and all examples, or exemplary language (e.g., “such as”)provided herein, is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention unlessotherwise claimed. No language in the specification should be construedas indicating any non-claimed element as essential to the practice ofthe invention.

Preferred embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention.Variations of those preferred embodiments may become apparent to thoseof ordinary skill in the art upon reading the foregoing description. Theinventors expect skilled artisans to employ such variations asappropriate, and the inventors intend for the invention to be practicedotherwise than as specifically described herein. Accordingly, thisinvention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

1. A compound of formula (I), its tautomeric form, its isomer, or itspharmaceutically acceptable salt,

wherein, A is selected from —CR⁷═, —C(H)(R⁷)— and —O—; B is selectedfrom —C(R⁷)═ and —S—; U is selected from —N═ and —S—; with a provisothat B and U both cannot be S at the same time; “

” represents a single or double bond; R¹ and R⁴ are divalent groups,each of which along with the respective carbon atoms to which they areattached form a 3 to 7 membered carbocyclic ring or a 5 to 7 memberedheterocyclic ring containing nitrogen, and optionally oxygen; R² and R³are each independently selected from hydrogen, substituted- orunsubstituted-alkyl, substituted- or unsubstituted-cycloalkyl,substituted- or unsubstituted-aryl, substituted- orunsubstituted-heteroaryl, substituted- or unsubstituted-heterocyclyl,R^(8a)C(═O)—, R^(8a)S(═O)₂—, R^(8a)OC(═O)—, (R⁹)R⁸NC(═O)—,R^(8a)OC(═O)_(N)(R⁹)CR^(b)(R^(a))C(═O)—,R^(8a)OC(═O)N(R⁹)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—,R^(8a)C(═O)N(R⁹)C(R^(b))(R^(a))C(═O)—,R^(8a)C(═O)N(R⁹)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—,(R⁹)R⁸NC(═O)N(R¹⁰)C(R^(b))(R^(a))C(═O)—, andR⁹(R⁸)NC(═O)N(R¹⁰)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—; R⁵ and R⁶ are eachindependently selected from hydrogen, halogen, substituted- orunsubstituted-alkyl, and substituted- or unsubstituted-cycloalkyl; R⁷ isselected from hydrogen, halogen, and substituted- or unsubstituted C₁₋₃alkyl; R⁸ is selected from hydrogen, substituted- orunsubstituted-alkyl, substituted- or unsubstituted-cycloalkyl,substituted- or unsubstituted-aryl, substituted- orunsubstituted-heteroaryl, and substituted- orunsubstituted-heterocyclyl; R⁹ and R¹⁰ are each independently selectedfrom hydrogen and substituted- or unsubstituted-alkyl; R^(8a) isindependently selected from the group consisting of substituted- orunsubstituted-alkyl, substituted- or unsubstituted-cycloalkyl,substituted- or unsubstituted-aryl, substituted- orunsubstituted-heteroaryl, and substituted- orunsubstituted-heterocyclyl; R^(a), R^(b), R^(c) and R^(d), areindependently selected from hydrogen, substituted- or unsubstituted-C₁₋₆alkyl, substituted- or unsubstituted-aryl, substituted- orunsubstituted-heteroaryl, substituted- or unsubstituted-cycloalkyl, andsubstituted- or unsubstituted-heterocyclyl, or R^(a), R^(b), R^(c) andR^(d) together with the carbon atom(s) to which they are attachedforming substituted- or unsubstituted-carbocycle, or substituted- orunsubstituted-heterocycle; m and n are integers independently selectedfrom 0 and 1; q is an integer selected from 1, 2, and 3; when the alkylgroup is a substituted alkyl group, the alkyl group is substituted with1 to 4 substituents selected independently from oxo, halogen, cyano,perhaloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, R^(11a)O—,(alkyl)S(═O)₂—, (alkyl)C(═O)—, (alkyl)OC(═O)—, (alkyl)C(═O)O—,R¹¹N(H)C(═O)—, R¹¹(alkyl)NC(═O)—, (alkyl)C(═O)N(H)—, R¹¹N(H)—,R¹¹(alkyl)N—, R¹¹(H)NC(═O)N(H)—, and R¹¹(alkyl)NC(═O)N(H)—; when the‘cycloalkyl’ and the carbocyclic groups are substituted, each of them issubstituted with 1 to 3 substituents selected independently from oxo,halogen, cyano, C₁₋₆ alkyl, perhaloalkyl, R^(11a)O—, (alkyl)S(═O)₂—,(alkyl)C(═O)—, (alkyl)OC(═O)—, (alkyl)C(═O)O—, R¹¹(H)NC(═O)—,R¹¹(alkyl)NC(═O)—, (alkyl)C(═O)N(H)—, R¹¹(H)N—, R¹¹(alkyl)N—,R¹¹(H)NC(═O)N(H)—, and R¹¹(alkyl)NC(═O)N(H)—; when the aryl group issubstituted, it is substituted with 1 to 3 substituents selectedindependently from halogen, cyano, hydroxy, C₁₋₆ alkyl, perhaloalkyl,alkyl-O—, perhaloalkyl-O—, alkyl(alkyl)N—, alkyl(H)N—, H₂N—,alkyl-S(═O)₂—, alkyl-C(═O)(alkyl)N—, alkyl-C(═O)N(H)—,alkyl(alkyl)NC(═O)—, alkyl(H)NC(═O)—, H₂NC(═O)—, alkyl(alkyl)NS(═O)₂—,alkyl(H)NS(═O)₂—, and H₂NS(═O)₂—; when the heteroaryl group issubstituted, it is substituted with 1 to 3 substituents selectedindependently from halogen, cyano, hydroxy, C₁₋₆ alkyl, perhaloalkyl,alkyl-O—, perhaloalkyl-O—, alkyl(alkyl)N—, alkyl(H)N—, H₂N—,alkyl-S(═O)₂—, alkyl-C(═O)(alkyl)N—, alkyl-C(═O)N(H)—,alkyl(alkyl)NC(═O)—, alkyl(H)NC(═O)—, H₂NC(═O)—, alkyl(alkyl)NS(═O)₂—,alkyl(H)NS(═O)₂—, and H₂NS(═O)₂—; when the heterocyclic group issubstituted, it can be substituted either on a ring carbon atom or on aring hetero atom, and when it is substituted on a ring carbon atom, itis substituted with 1-3 substituents selected independently fromhalogen, cyano, oxo, C₁₋₆ alkyl, perhaloalkyl, R^(11a)O—,(alkyl)OC(═O)—, (alkyl)C(═O)O—, R¹¹(H)NC(═O)—, R¹¹(alkyl)NC(═O)—,(alkyl)C(═O)N(H)—, R¹¹(H)N—, R¹¹(alkyl)N—, R¹¹(H)NC(═O)N(H)—, andR¹¹(alkyl)NC(═O)N(H)—; and when the ‘heterocyclic’ group is substitutedon a ring nitrogen, it is substituted with a substituent selected from—C₁₋₆ alkyl, (alkyl)SO₂—, (alkyl)C(═O)—, (alkyl)OC(═O)—, R¹¹(H)NC(═O)—,and R¹¹(alkyl)NC(═O)—; R¹¹ is selected from hydrogen, alkyl, cycloalkyl,aryl, heteroaryl, and heterocyclyl; R^(11a) is selected from hydrogen,alkyl, perhaloalkyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl. 2.The compound of formula (I), its tautomeric form, its isomer, or itspharmaceutically acceptable salt, as claimed in claim 1, wherein thecompound of formula I is selected from


3. The compound of formula (I), its tautomeric form, its isomer, or itspharmaceutically acceptable salt, as claimed in claim 1, wherein R¹ andR⁴ are C₁₋₄ alkylenyl.
 4. The compound of formula (I), its tautomericform, its isomer, or its pharmaceutically acceptable salt, as claimed inclaim 1, wherein R² and R³ are each independently selected fromR^(8a)C(═O)—, R^(8a)S(═O)₂—, R^(8a)OC(═O)—, (R⁹)R⁸NC(═O)—,R^(8a)OC(═O)N(R⁹)CR^(b)(R^(a))C(═O)—,R^(8a)OC(═O)N(R⁹)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—,R^(8a)C(═O)N(R⁹)C(R^(b))(R^(a))C(═O)—,R^(8a)C(═O)N(R⁹)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—,)(R⁹)R⁸NC(═O)N(R¹⁰)C(R^(b))(R^(a))C(═O)—,and R⁹(R⁸)NC(═O)N(R¹⁰)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—.
 5. Thecompound of formula (I), its tautomeric form, its isomer, or itspharmaceutically acceptable salt, as claimed in claim 1, wherein R² andR³ are each independently selected fromR^(8a)OC(═O)N(R⁹)CR^(b)(R^(a))C(═O)—,R^(8a)OC(═O)N(R⁹)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—,R^(8a)C(═O)N(R⁹)C(R^(b))(R^(a))C(═O)—,R^(8a)C(═O)N(R⁹)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—,)(R⁹)R⁸NC(═O)N(R¹⁰)C(R^(b))(R^(a))C(═O)—,and R⁹(R⁸)NC(═O)N(R¹⁰)CR^(b)(R^(a))C(R^(d))(R^(c))C(═O)—.
 6. Thecompound of formula (I), its tautomeric form, its isomer, or itspharmaceutically acceptable salt, as claimed in claim 1, wherein R² andR³ both are selected as R^(8a)OC(═O)N(R⁹)CR^(b)(R^(a))C(═O)—.
 7. Thecompound of formula (I), its tautomeric form, its isomer, or itspharmaceutically acceptable salt, as claimed in claim 1, wherein R⁵ andR⁶ are selected independently from hydrogen and halogen.
 8. The compoundof formula (I), its tautomeric form, its isomer, or its pharmaceuticallyacceptable salt, as claimed in claim 1, wherein the compound is selectedfromdimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,9b-dihydro-3aH-thieno[3,2-c]chromene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate;dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate;dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2,8-diyl)bis(4-chloro-1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate;dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(naphtho[1,2-d]thiazole-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate;dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate;dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(3-chloro-4,5-dihydronaphtho[1,2-b]thiophene-2,7-diyebis(4-chloro-1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate;dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate;dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)bis(1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate;dimethyl((2S,2′S)-((2S,2′S)-2,2′-(5,5′-(5,6-dihydro-4H-benzo[6,7]cyclohepta[1,2-b]thiophene-2,8-diyl)bis(4-chloro-1H-imidazole-5,2-diyl))bis(pyrrolidine-2,1-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate;dimethyl((2S,2′S)-((1R,1′R,3S,3′S,4S,4′S)-3,3′-(5,5′-(naphtho[1,2-b]thiophene-2,7-diyl)bis(1H-imidazole-5,2-diyl))bis(2-azabicyclo[2.2.1]heptane-3,2-diyl))bis(3-methyl-1-oxobutane-2,1-diyl))dicarbamate;andmethyl((S)-1-((S)-2-(5-(2-(2-((1R,3S,4S)-2-((S)-2-(methoxycarbonyl)amino-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphtho[1,2-b]thiophen-7-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate.9. A pharmaceutical composition comprising a compound or a combinationof compounds according to claim 1, a tautomeric form, an isomer, or apharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable carrier or excipient.
 10. A method ofinhibiting the replication of an RNA-containing virus comprisingcontacting said virus with a therapeutically effective amount of acompound or combination of compounds according to claim 1, a tautomericform, an isomer, or a pharmaceutically acceptable salt thereof.
 11. Amethod of treating or preventing infection caused by an RNA-containingvirus comprising administering to a patient in need of such treatment orprevention a therapeutically effective amount of a compound orcombination of compounds according to claim 1, a tautomeric form, anisomer, or a pharmaceutically acceptable salt thereof.
 12. The method ofclaim 11, wherein the RNA-containing virus is hepatitis C virus.
 13. Themethod of claim 11, further comprising the step of co-administering oneor more agents selected from a host immune modulator and an antiviralagent, or a combination thereof.
 14. The method of claim 13, wherein thehost immune modulator is selected from interferon-alpha,pegylated-interferon-alpha, interferon-beta, interferon-gamma, consensusinterferon, a cytokine, and a vaccine.
 15. The method of claim 13,wherein the antiviral agent inhibits replication of HCV by inhibiting ahost cellular function associated with viral replication.
 16. The methodof claim 13, wherein the antiviral agent inhibits the replication of HCVby targeting a protein of the viral genome.
 17. The method of claim 13,wherein said antiviral agent is an inhibitor of a HCV viral protein, areplication process, or a combination thereof, wherein said targetingprotein or replication process is selected from helicase, protease,polymerase, metalloprotease, NS4A, NS4B, NS5A, assembly, entry, andIRES.
 18. The method of claim 13, further comprising the step ofco-administering an agent or combination of agents that treat oralleviate symptoms of HCV infection selected from cirrhosis andinflammation of the liver.
 19. The method of claim 13, furthercomprising the step of co-administering one or more agents that treatpatients for disease caused by hepatitis B (HBV) infection.
 20. Themethod of claim 13, further comprising the step of co-administering oneor more agents that treat patients for disease caused by humanimmunodeficiency virus (HIV) infection.
 21. The pharmaceuticalcomposition of claim 9, further comprising an agent selected frominterferon, pegylated interferon, ribavirin, amantadine, an HCV proteaseinhibitor, an HCV polymerase inhibitor, an HCV helicase inhibitor, or aninternal ribosome entry site inhibitor.
 22. The composition of claim 9,further comprising a cytochrome P450 monooxygenase inhibitor or apharmaceutically acceptable salt thereof.
 23. A method of treatinghepatitis C infection in a subject in need thereof comprisingco-administering to said subject a cytochrome P450 monooxygenaseinhibitor or a pharmaceutically acceptable salt thereof, and a compoundof claim 1, a tautomeric form, an isomer, or a pharmaceuticallyacceptable salt thereof.
 24. (canceled)